Association of CYP3A4 in Cancer OccurrenceSeverity and Drug Metabolism

Association of CYP3A4 in cancer occurrence severity and drug metabolism Abstract The CYP3A genes reside on chromosome 7q21 in a multigene cluster. The enzyme products of CYP3A4 and CYP3A43 are involved in testosterone metabolism. CYP3A4 and CYP3A5 have been associated with prostate cancer occurrence and severity. It has been estimated that up to 60% of the variability in CYP3A4 activity may be because of a genetic component. A SNP in the nifedipine-specific response element in the promoter of the CYP3A4 gene (alternatively termed eg. -392AG, CYP3A4-V, CYP3A41B).

Case studies of Caucasians and of African-Americans have detected associations between CYP3A41B and presentation with biologically aggressive disease. It has been postulated that the presence of the CYP3A41B allele decreases the amount of CYP3A4 protein, leading to a reduction of testosterone metabolism and, therefore, more availability of testosterone for conversion to dihydrotestosterone, the most potent androgen affecting the growth and differentiation of prostate cells, including an intronic SNP that affects splicing of the CYP3A5 transcript.

The observation that CYP3A4 and CYP3A43 were associated with prostate cancer, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and CYP3A43*3 may influence the probability of having prostate cancer and disease severity. Also variability in CYP3A4 function was determined noninvasively by the erythromycin breath test (ERMBT) and lead to the detection of role of CYP3A4 in causing prostate and breast cancer. Cytochrome P450 3A4 (CYP3A4) is the major enzyme responsible for phase I drug metabolism of many anticancer agents.

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It is also a major route for metabolism of many drugs used by patients to treat the symptoms caused by cancer and its treatment as well as their other illnesses, for example, cardiovascular disease. Advanced cancer patients are on multiple medications for symptom management and co-morbidities. Pharmacokinetic drug interactions occur with absorption, drug–protein binding, metabolism, and elimination. By far the most prevalent and dangerous drug–drug interactions occur through cytochrome metabolism.

Drug metabolism is through the cytochrome system (phase I) and/or through conjugation (phase II). Cyto- chromes oxidize, demethylate, or hydroxylate substrate medications and conjugases increase drug solubility by adding glucuronides, amino acids, or sulfate subgroups that facilitate elimination. In this review, I also examine the role of specific P450 enzymes in the metabolism of anticancer drugs in humans and discuss some significant interactions that often appear to result from inhibition of anticancer drug metabolism.

The available evidence, however, strongly suggests that certain drugs influence the pharmacokinetics of anticancer agents also (and perhaps primarily) by acting as P-glycoprotein inhibitors, thereby inhibiting P-glycoprotein mediated drug elimination. CYP3A4 metabolizes a large number of anticancer drugs and patients are generally prescribed other medications to relieve symptoms (e. g. , analgesics) and side effects (e. g. , antiemetics and antidiarrheals) and to treat comorbidities. The anti- cancer drugs metabolized by CYP3A4 include docetaxel (Marre et al. , 1996), cyclophosphamide (Chang et al. 1993), ifosfamide (Walker et al. , 1994), etoposide (Kawashiro et al. , 1998), tamoxifen (Crewe et al. , 1997), irinotecan (Santos et al. , 2000), vinblastine (Zhou-Pan et al. , 1993), and vinorelbine (Kajita et al. , 2000). Although there is a marked interindividual variation of pharmacokinetic parameters be-tween patients (Evans and Relling, 1999), and such variation in patient response is often attributed to polymorphism in P450 genes, CYP3A4 is an exception because only a small percentage of the variation in activity can be attributed to genotype (Lamba et al. , 2002a,b).

Introduction

Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1. 14. 13. 97), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. CYP3A4 is also, correspondingly, present in the largest quantity of all the CYPs in the liver. Although CYP3A4 is predominantly found in the liver, it is also present in other organs and tissues of the body where it may play an important role in metabolism.

Recently CYP3A4 has also been identified in the brain, however its role in the central nervous system is still unknown. The CYP3A genes lie in a region of chromosome 7q21-q22 as part of a multigene family, including CYP3A4, CYP3A5, CYP3A7, CYP3A43 in addition to psuedogenes. Only CYP3A4, CYP3A5, CYP3A7, and CYP3A43 are expressed in adults. These loci seem to be in linkage disequilibrium. [pic] While over 28 single nucleotide polymorphisms (SNPs) have been identified in the CYP3A4 gene, it has been found that this does not translate into significant interindividual variability in vivo.

It can be supposed that this may be due to the induction of CYP3A4 on exposure to substrates. CYP3A4 is responsible for the oxidative metabolism of a wide variety of xenobiotics, including an estimated 60% of all clinically used drugs. Although expression of the CYP3A4 gene is known to be induced in response to a variety of compounds, the mechanism underlying this induction, which represents a basis for drug interactions in patients.

CYP3A4 is expressed in the prostate, breast, gut, colon, and small intestine, but its expression is most abundant in the human liver, accounting for 30 percent of the total CYP protein content. It exhibits a broad substrate specificity and is responsible for oxidation of many therapeutic drugs and a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In liver microsomes, it is involved in a nicotinamide adenine dinucleotide phosphate-dependent electrontransport pathway.

Prostate cancer is an abnormal, uncontrolled growth of cells that results in the formation of a tumor in the prostate gland. Prostate cancer begins most often in the outer part of the prostate. It is the most common cancer in men older than age 50. In most men, the cancer grows very slowly. Genes involved in androgen metabolism have been implicated in the etiology of prostate cancer. Testosterone is a major determinant of prostate growth and differentiation. Testosterone bioavailabilty is determined by a number of enzymes, including CYP3A4 and CYP3A43.

CYP3A4 is involved in the oxidation of testosterone to 2-, 6-, or 15-hydroxytestosterone (which is less biologically active than testosterone or dihydrotestosterone. CYP3A43 also exhibits testosterone 6-hydroxylation in vitro and is predominantly expressed in the prostate. Variants that affect CYP3A4 activity could therefore alter prostate tumor occurrence or aggressiveness. A variant in the 5’untranslated region of CYP3A4 (denoted CYP3A4*1B) has been associated with prostate cancer in three studies.

A mutation in CYP3A4 may lead to a reduced potential for oxidizing testosterone, leaving a greater bioavailability of the hormone to be metabolized intracellularly to its biologically active form of dihydroxytestosterone, the principal androgenic hormone involved in regulating prostate growth. Clinical evidence exists that androgens are related to the growth and development of prostate cancers, and Androgen ablation in men with hormone-sensitive prostate tumors reduces tumor size and decreases the associated disease burden.

This evidence suggests that the metabolism of testosterone into the more biologically active forms of the hormone may be important in determining prostate cancer risk. Medications are metabolized and secreted through the liver, gastrointestinal tract, and kidneys, all of which contain cytochrome enzymes for this purpose. The kidneys do not efficiently eliminate lipophilic drugs that are readily reabsorbed across tubular membranes in the distal renal collecting system; conjugation of drugs improves solubility and drug elimination.

Lipid-soluble agents are first metabolized by two reactions termed phase I and phase II before being eliminated. The phase I enzymes most frequently involved are cytochromes CYP3A4/3A5, CYP2D6, CYP2C9, CYP2C19 . Cytochrome-induced oxidation hydroxylation and demethylation proceeds by initial binding of drug to the oxidized form of cytochrome P450, and then coupling NADPH-bound oxygen to the cytochrome P450 oxidoreductase. Common medications used in palliative medicine (dexamethasone, prednisone, midazolam, triazolam, alprazolam, methadone, fentanyl, and haloperidol) are substrate drugs for CYP3A4.

Certain anti-seizure drugs, selective serotonin receptor inhibitors, macrolides, and azoles either upregulate or inhibit CYP3A4 enzyme activity. Protease inhibitors and nucleoside or non-nucleoside analogs used for anti-retroviral therapy can both inhibit enzyme activity and/or upregulate CYP3A4 expression.

Factors influencing drug interactions of CYP3A4

• Recipient drug concentrations
• Enzyme saturation relative to concentration of recipient drug at enzyme site
• Substrate drug affinity for the enzyme (Km) and enzyme capacity (Vmax)
• Homotropic enzyme interactions by recipient drug Concentration of the precipitant drug in liver vs plasma
• Inhibition constant relative to inhibitor concentration
• Precipitant drug interactions at both promoter site and the structural enzyme site
• Liver concentration of precipitant drug and recipient drug(recipient and precipitant drug) clearance through multiple organs or cytochromes
• Contribution of P-glycoprotein to recipient and precipitant drug metabolism and elimination
• Genetically determined expression of CYP3A4 governed by the promoter site.

Specific cytochrome P450 (CYP) enzymes have been recently shown to be involved in the metabolism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer drugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide could be activated in tumour tissues containing this enzyme. As xamples of recently found, clinically significant interactions, cyclosporin considerably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhibitors inhibit P-glycoprotein mediated drug elimination. Appropriate caution should be exercised when combining P-glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy.

Studies have shown that P450 enzymes are expressed not only in the liver and extrahepatic tissues but also in different kinds of tumours. For example, the prodrugscyclophosphamide and ifosfamide need to be activated by specific P450 enzymes to produce cytotoxic compounds, and, if these enzymes were also found in the tumour, local activation of the drug could be important for efficacy. In selected cases, it might even be possible to enhance drug activation through modulation of the appropriate P450 enzyme(s).

If bioactivation in the liver is predominant, the question arises whether the active metabolite(s) can achieve effective concentrations in the tumour. The delivery of the drug or the active metabolites into the tumour may be inadequate, for instance, due to the physicochemical nature of the compound or poor vascularization of the tumour. When evaluating the potential significance of drug interactions with anticancer drugs, the key question is whether such interactions could affect, at least in selected cases, the overall clinical response or toxicity of the drug.

In general, the pharmacological properties of anticancer drugs (e. g. steep dose-response curves and low therapeutic indices) suggest that even small changes in the pharmacokinetic profile could significantly alter toxicity or efficacy. Material and Methods Lehmann et al. (1998) identified a human orphan nuclear receptor, termed the pregnane X receptor, that binds to a response element in the CYP3A4 promoter and is activated by a range of drugs known to induce CYP3A4 expression. It is inducible by a variety of agents including glucocorticoids and phenobarbital.

It appears to play a central role in the metabolism of the immunosuppressive cyclic peptide cyclosporin A as well as macrolide antibiotics, such as erythromycin. It also catalyzes the 6-beta-hydroxylation of a number of steroids including testosterone, progesterone, and cortisol. As indicators of CYP3A4 function in the evaluation of transplant recipients, measurement of erythromycin metabolism by a breath test (Elshourbagy and Guzelian, 1980) and the presence of 6-beta-hydroxylated steroids in urine have been used. This has led to study the role of CYP3A4 in causing prostate cancer.

Similar experiments were performed for females which showed its role in the occurrence of breast cancer. Shet et al. (1993) reported the results of experiments designed to evaluate the enzymatic properties of a purified recombinant fusion protein containing the heme domain of human CYP3A4. Epipodophyllotoxins, which are used as DNA topoisomerase II inhibitors in the treatment of leukemia and are associated with the production of translocations involving the MLL gene as well as of other translocations, are substrates for metabolism by CYP3A. Rebbeck et al. 1998) identified a variant in the 5-prime promoter region of the CYP3A4 gene: a polymorphism in the nephedipine-specific response element of the gene. They referred to the polymorphism as CYP3A4-V or CYP3A4*1B. There are several pathways involved in the metabolism of testosterone, and the genes that regulate these pathways, including 5-alpha-reductase-2 (SRD5A2) and CYP3A4, have been implicated in prostate cancer susceptibility. The CYP3A4*1B allele may decrease the oxidative deactivation of testosterone (Rebbeck et al. , 1998). African Americans have the highest documented rates of prostate cancer in the world.

Zeigler-Johnson et al. (2002)studied differences in genotypes at the SRD5A2 and CYP3A4 loci according to ethnicity. They found that the CYP3A4*1B allele was more common in Ghanaians and African Americans (gene frequency more than 50%) than in Caucasians (less than 10%), and was apparently nonexistent in Asians. Schirmer et al. (2006) investigated the CYP3A locus in 5 ethnic groups. The degree of linkage disequilibrium (LD) differed among ethnic groups, but the most common alleles of the conserved LD regions were remarkably similar.

Non-African haplotypes were few; for example, only 4 haplotypes accounted for 80% of common European Caucasian alleles. Large LD blocks of high frequencies suggested selection. European Caucasian and Asian cohorts each contained a block of single-nucleotide polymorphisms with very high P excess values. The overlap between these blocks in these 2 groups contained only 2 of the investigated 26 SNPs, and 1 of them was the CYP3A41B allele. The region centromeric of CYP3A4*1B on 7q exhibited high haplotype homozygosity in European Caucasians as opposed to African Americans.

CYP3A4*1B showed a moderate effect on CYP3A4 mRNA and protein expression, as well as on CYP3A activity assessed as V(max) of testosterone 6-beta-hydroxylation in a liver bank. Selection against the CYP3A4*1B allele in non-African populations was suggested. The elimination of this allele involved different parts of the CYP3A locus in European Caucasians and Asians. Because CYP3A4 is involved in vitamin D metabolism, Schirmer et al. (2006) raised the possibility that rickets might be the underlying selecting factor.

By genotyping liver samples from 18 Caucasian donors at 2 SNPs (78013C-T and 78649C-T) in intron 7 of CYP3A4, Hirota et al. (2004) demonstrated a correlation between the total CYP3A4 mRNA level and allelic expression ratio, defined as the relative transcript level ratio derived from the 2 alleles. Individuals with a low expression ratio, exhibiting a large difference of transcript level between the 2 alleles, revealed extremely low levels of total hepatic CYP3A4 mRNA, and thus low metabolic capability as assessed by testosterone 6-beta-hydroxylation.

A broad specificity coupled with high levels of expression in the liver means it is responsible for the metabolism of more than half of all prescribed drugs (Guengerich, 1997). When patients receive several medications concurrently, unwanted and life-threatening effects can result from the competition for the same drug-metabolizing enzyme affecting the blood levels of the competing drugs. Cancer patients would seem to be significantly at risk in this respect, because CYP3A4 metabolizes a large number of anticancer drugs and patients are generally prescribed other medications to relieve symptoms (e. g. analgesics) and side effects (e. g. , antiemetics and antidiarrheals) and to treat comorbidities. The anti-cancer drugs metabolized by CYP3A4 include docetaxel (Marre et al. , 1996), cyclophosphamide (Chang et al. , 1993), ifosfamide (Walker et al. , 1994), etoposide (Kawashiro et al. , 1998), tamoxifen (Crewe et al. , 1997), irinotecan (Santos et al. , 2000), vinblastine (Zhou-Pan et al. , 1993), and vinorelbine (Kajita et al. , 2000). [pic] Cyclophosphamide and ifosfamide Cyclophosphamide and ifosfamide are alkylating anticancer agents that require biotransformation to produce pharmacologically active, cytotoxic compounds.

Chang and colleagues demonstrated that CYP2B6 and CYP3A4 are the major isoforms catalyzing cyclophosphamide and ifosfamide 4-hydroxylation (that is, activation), respectively, in human liver. Walker et al. recently showed that CYP3A4 makes a significant contribution to both the activation and N-dechloroethylation of ifosfamide in human liver. Ifosfamide (IF) is a widely used antitumor prodrug that is effective against solid tumors such as sarcomas and hematologic malignancies.

Major clinical toxicities include urotoxicity, nephrotoxicity and neurotoxicity (occurs in approximately 20% of patients). On the other hand, IF has lower myelotoxicity relative to its structural analog, cyclophosphamide. Glomerular and tubular dysfunctions represent serious side effects, especially in children who are co-treated with other nephrotoxic drugs. This diagram, which shows the genes involved in the biotransformations of IF and its metabolites, includes pathways of activation, deactivation and toxicity.

The metabolism of IF is parallel to that of cyclophosphamide but with some differences in isozyme specificities and reaction kinetics. Activation of IF to 4-hydroxyifosfamide is catalyzed by the hepatic cytochrome P450 (CYP) isoform CYP3A4 with 2A6, 2B6, 2C8, 2C9 and 2C19 making more minor contributions. Competing with 4-hydroxylation is a major (up to 50% or more) oxidative pathway that results in dechloroethylation and the formation of chloroacetaldehyde (neurotoxic) and 2- or 3-dechloroethylifosfamide (primarily mediated by CYP2B6 and CYP3A4). -Hydroxyifosfamide rapidly interconverts with its tautomer, aldoifosfamide. It is likely that both of these metabolites passively diffuse out of hepatic cells, circulate, and then passively enter other cells. Aldoifosfamide partitions between ALDH1A1-mediated detoxification to carboxyifosfamide and a spontaneous (non-enzymatic) elimination reaction to yield isophosphoramide mustard (IPM) and acrolein (associated with bladder toxicity).

IPM, the DNA crosslinking agent of clinical significance, is a circulating metabolite but the anionic IPM does not enter cells as readily as its metabolic precursors. Thus, the intracellular generation of IPM from aldoifosfamide is generally believed to be important to a therapeutic result. Multiple IF metabolites can react with glutathione (GSH) resulting in the formation of various conjugates at different sites along the pathway. Some of these reactions with GSH may be reversible while others are irreversible; the latter are associated with detoxification pathways.

Large interpatient differences, which may be up to seven-fold, in the pharmacokinetics and biotransformation of IF have been reported; however, there has been little reported about genetic variations that may influence varied response to IF treatment. Like cyclophosphamide, IF is chiral at phosphorus but unlike the case for cyclophosphamide, enantioselectivity in IF metabolism may have clinical significance. This is particularly relevant to the distribution of 4-hydroxylation versus N-dechloroethylation products and the impact of this on the CNS toxicity associated with IF therapy.

The differences in the metabolism and disposition of the R- and S-enantiomers of IF have not been fully evaluated in human tissues. Nevertheless, in several studies using characterized human liver microsomes or cDNA-expressed isozymes it has been shown that (R)-IF is subject to less dechloroethylation and more rapid 4-hydroxylation relative to the (S)-IF. Cyclophosphamide (CP) is a widely used antitumor prodrug that is effective against a broad spectrum of human cancers including breast cancer and lymphomas.

The toxicity profile is characterized by myelosuppression and urotoxicity. This diagram shows the genes involved in the biotransformation of CP and its metabolites and includes pathways of activation, deactivation and toxicity. Activation of CP to 4-hydroxycyclophosphamide is catalyzed by the hepatic cytochrome P450 (CYP) isozymes CYP2B6, 2C9 and 3A4 (with 2A6, 2C8 and 2C19 making more minor contributions). Competing with C-4 hydroxylation of CP is a minor (~10%) oxidative pathway that leads to N-dechloroethylation and the formation of the neurotoxic chloroacetaldehyde.

CYP3A4 is primarily responsible for this undesirable side-chain oxidation with a minor contribution from CYP2B6. 4-Hydroxycyclophosphamide interconverts rapidly with its tautomer, aldophosphamide and it is likely that both of these metabolites passively diffuse out of hepatic cells, circulate, and then passively enter other cells. Aldophosphamide undergoes a spontaneous (non-enzymatic) elimination reaction to yield phosphoramide mustard (PM) and acrolein (associated with bladder toxicity).

PM, which is generally believed to be the DNA crosslinking agent of clinical significance, is a circulating metabolite with its anionic form not entering cells very easily. Thus, the intracellular generation of PM from aldophosphamide is believed to be important to a therapeutic result. A major detoxification route is the oxidation of aldophosphamide to the inactive carboxyphosphamide by ALDH1A1 and, to a much lesser extent, by ALDH3A1 and ALDH5A1. Multiple CP metabolites can react with glutathione (GSH) resulting in the formation of various conjugates at different sites along the pathway.

Some of these reactions with GSH may be reversible while others are irreversible; the latter are associated with detoxification pathways. Several-fold differences in the extent of metabolite formation have been observed among patients and these inter-individual differences may be due to polymorphisms in CYP enzymes. There are reports of association between CYP3A4 and 3A5 genotypes and response or survival in patients treated with CP. Many of the genetic variants that affect CP metabolism may still be unknown and further evidence of these variants will be needed to better assess clinical outcomes.

It is noteworthy that CP is chiral at phosphorus and is administered as a racemate; however, enantioselectivity in the metabolism of CP does not appear to result in clinical significance.

Irinotecan

This pathway shows the biotransformation of the chemotherapy prodrug irinotecan to form the active metabolite SN-38, an inhibitor of DNA topoisomerase I. SN-38 is primarily metabolized to the inactive SN-38 glucuronide by UGT1A1, the isoform catalyzing bilirubin glucuronidation. Irinotecan is used in the treatment of metastatic colorectal cancer, small cell lung cancer and several other solid tumors. pic] There is large interpatient variability in response to irinotecan, as well as severe side effects such as diarrhea and neutropenia, which might be explained in part by genetic variation in the metabolic enzymes and transporters depicted here. Well-known variants to effect this pathway are the promoter polymorphic repeat in UGT1A1 (UGT1A128) and the 1236C>T polymorphism in ABCB1. While UGT1A1*28 genotype has been associated with toxicity, further evidence is needed to describe the roles of ABCB1 variants in toxicity.

Epipodophyllotoxins

Relling et al. recently showed that catechol formation by O-demethylation from teniposide and etoposide is primarily mediated by CYP3A4 in human liver. Several substrates for CYP3A4 (e. g. midazolam, erythromycin and cyclosporin) were identified as strong inhibitors of catechol formation from both etoposide and teniposide. The extent of contribution of 0-demethylation to the overall in vivo elimination of these agents is not known, but catechol formation appears to play only a relatively small role in the metabolism of the epipodophyllotoxins.

However, the catechols of epipodophyllotoxins are cytotoxic, and it has been suggested that cytotoxic concentrations of the catechol metabolites might be achieved clinically. Etoposide and teniposide, the epipodophyllotoxins, stabilize the double stranded DNA cleavage normally catalyzed by topoisomerase II and inhibit faithful religation of DNA breaks (PMID: 1681541; 9748545). These double-strand DNA breaks subsequently trigger the desired antitumor effects of the drugs. Metabolism of etoposide is mediated by CYP3A4 and CPY3A5 (PMID: 8114683; 15319341), both of which are transcriptionally regulated by NR1I2 i. e. Pregnane X receptor). Thus, xenobiotics that modulate NR1I2 activity (e. g. dexamethasone and rifampicin) have been observed to enhance etoposide clearance (PMID: 15578943; 12969965). In addition to CYP3A4/5 mediated reactions, conversion of etoposide to the O-demethylated metabolites (catechol and quinone) can also be catalyzed by prostaglandin synthases or myeloperoxidase.

Glutathione and glucuronide conjugation appear to inactivate parent drug and metabolite, and are mediated by GSTT1/GSTP1 and UGT1A1, respectively (PMID: 1315544; 3167829; 17151191; 12695346). Efflux of conjugated or unconjugated forms of etoposide has been associated with ABCC1, ABCC3 and ABCB1 (PMID: 8640791; 11581266), representing plausible mechanisms of drug resistance. Epipodophyllotoxins are highly effective anticancer agents, but can cause a delayed toxicity: treatment-related acute myeloid leukemia or myelodysplastic syndrome (t-ML) (PMID: 18509329; 1944468; 2822173).

Drug-induced formation of MLL fusion genes has been associated with the development of t-ML (PMID: 8260707). Even though etoposide inhibits both topo II alpha and beta, the anti-tumor activity of etoposide is shown to be delivered primarily through inhibition of topo II alpha (PMID: 11531262) whilst the carcinogenic effect has been attributed to the beta isoform (PMID: 17578914). Recently, 64 genetic variants that contribute to etoposide-induced cytotoxicity were identified through a whole-genome association study (PMID: 17537913).

Tamoxifen

Tamoxifen, a selective estrogen receptor modulator (SERMs), is important for the treatment and prevention of breast cancer. Tamoxifen is extensively metabolized predominantly by the cytochrome P450 (CYP) system to several primary and secondary metabolites. Some of these metabolites exhibit more antiestrogenic effect in breast cancer cells than tamoxifen itself. The pathway depicts major pathways of tamoxifen metabolism that might have relevance to tamoxifen activity. Tamoxifen 4-hydroxylation is the most studied because it has been shown that 4-hydroxy-tamoxifen is approximately 30- to 100-fold more potent antiestrogen than tamoxifen.

Tamoxifen 4-hydroxylation is catalyzed by CYP2D6 and other isoforms.  The major metabolic pathway of tamoxifen is N-demethylation to N-desmethyltamoxifen. This pathway is primarly catalyzed by CYP3A4 and CYP3A5. N-Desmethyltamoxifen is further oxidized to a number of metabolites that appear important to tamoxifen activity. First, N-desmethyltamoxifen is hydroxylated by the CYP2D6 enzyme to endoxifen. This metabolite is as potent as 4-hydroxytamoxifen in terms of antiestrogenic activity, while its plasma oncentrations in breast cancer patients is much higher than that of 4-hydroxytamoxifen. Second, N-desmethyltamoxifen undergoes sequential metabolism to metabolite E, which exhibit in vitro estrogenic activity. Anthracyclins Anthracyclines play an important role in the treatment of cancer, and doxorubicin was one of the first anthraycyclines isolated from Streptomyces peucetius. Doxorubicin is an essential part of treatment for breast cancer, childhood solid tumors, soft tissue sarcomas and aggressive lymphomas.

However, tumor cells quickly develop resistance to these drugs and healthy cells become toxic, the main toxic effect is cardiac failure. Doxorubicin is a cell cycle-specific drug that slows or stops the growth of cancer cells by inhibiting DNA synthesis in S phase. Its exact mechanism of antineoplastic activity is still unknown but may involve binding to DNA by intercalation between base pairs and inhibition of DNA and RNA synthesis. Taxol (paclitaxel) Harris et al. [64] have studied the metabolism of taxol in human hepatic microsomes.

Their findings suggest that CYP3A4 is the major catalyst of the formation of a minor metabolite of taxol, whereas the identity of the enzyme(s) responsible for 6-ac-hydroxytaxol formation could not be assigned with certainty. 6-ac-hydroxytaxol is the major, but inactive metabolite of this antitumour drug in humans. The results of Kumar et al. suggested that taxol 6-a-hydroxylation in human liver is mediated by CYP3A, but apparently not CYP3A4. Cresteil et al. , however, reported that 6-a- hydroxytaxol formation can be assigned to the CYP2C subfamily, a finding later confirmed by Rahman et al..

These investigators showed that, of several human P450 enzymes studied, only CYP2C8 formed detectable 6-a-hydroxytaxol. There was no interaction between doxorubicin and taxol. However, interactions resulting from induction or inhibition of P450 enzymes, especially CYP3A4 and CYP2C8, can be anticipated to occur in clinical practice. More studies about the effects of other drugs on taxol pharmacokinetics are awaited.  Docetaxel belongs to the class of taxane antineoplastic agents that act by inducing microtubular stability and disrupting the dynamics of the microtubular network.

The drug has shown a broad spectrum of antitumour activity in preclinical models as well as clinically, with responses observed in various disease types, including advanced breast cancer and non-small cell lung cancer. The pharmacokinetics and metabolism of docetaxel are extremely complex and have been the subject of intensive investigation in recent years. Docetaxel is subject to extensive metabolic conversion by the cytochrome P450 (CYP) 3A isoenzymes, which results in several pharmacologically inactive oxidation products.

Elimination routes of docetaxel are also dependent on the presence of drug-transporting proteins, notably P-glycoprotein, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, impact substantially on interindividual variability in drug handling. Strategies to individualise docetaxel administration schedules based on phenotypic or genotype-dependent differences in CYP3A expression are underway and may ultimately lead to more selective chemotherapeutic use of this agent. Medroxyprogesterone acetate (MPA)

Medroxyprogesterone acetate (MPA) is a drug commonly used in endocrine therapy for advanced or recurrent breast cancer and endometrial cancer. The drug is extensively metabolized in the intestinal mucosa and in the liver. Cytochrome P450s (CYPs) involved in the metabolism of MPA were identified by using human liver microsomes and recombinant human CYPs. Methadone and Antibiotics Methadone is subject to dangerous drug interactions at CYP3A4. Methadone is largely metabolized in the liver by CYP3A4 to the N-demethylated derivative EDDP (2- ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine).

CYP3A4 activity varies considerably between individuals, and this variability is responsible for the large differences in methadone clearance and doses needed for pain relief. Patients on methadone who are also on certain psychotropic drugs, antibiotics, antifungal, macrolides, anticonvulsants or antiretroviral drugs have a significant risk for pharmacokinetic interactions leading to opioid toxicity or withdrawal. Ciprofloxacin is commonly used for infections in cancer and is a potent inhibitor to CYP1A2, CYP2D6, and CYP3A4.

Profound sedation is reported with the combination of methadone and ciprofloxacin. Caution should be taken whenever ciprofloxacin is added to steady doses of methadone. CYP3A4 Inhibitor Antifungal medications Triazoles are used widely in cancer and palliative medicine to treat fungal infections and are potent inhibitors of CYP3A4. Itraconazole is the most potent inhibitor of commonly used triazole. Fluconazole at high doses has the same inhibition as itraconazole. Ketoconazole has the lowest Ki and the greatest inhibition of azoles but is less important because it is infrequently used.

Azole antifungals delay the clearance of certain benzodiazepines (diazepam, alprazolam, and midazolam), methadone, and fentanyl. Terbinafine has no significant CYP3A4 interactions and is preferred as an oral antifungal if patients are on CYP3A4 substrates. Discussion In adults, CYP3A4 and CYP3A5 are the most important among the four CYP3A subfamily members for CYP3A-mediated drug metabolism, and because of the genetic diversity in the genes encoding these proteins, genotyping for CYP3A4 and CYP3A5 variants may be useful for prediction of total hepatic CYP3A activity.

Genetic differences may also explain 60 to 90% of the observed variation in CYP3A4-mediated drug- metabolizing capacity between patients. Over 30 single nucleotide polymorphisms in CYP3A4 have been published, representing alleles CYP3A4*1 to CYP3A4*19, most of which are very rare and unlikely to impact on CYP3A4 activity in vivo. The best characterized variant, a promoter variant with an A to G transition at nucleotide 392 (CYP3A4*1B), was shown in vitro to have increased transcriptional activity.

A recent study showed a dose-dependent association between CYP3A5*3C genotype and plasma concentrations of ABT-773, where drug exposure was higher in probes midazolam, erythromycin, and nifedipine. One recent study involving a predominantly white population of 67 cancer patients observed 1. 7-fold higher midazolam clearance in 9 patients with the *1/*3 genotype at the CYP3A5*3C allele compared with 58 patients with the *3/*3 genotype. These data are not consistent with the present CYP3A5-negative individuals (those that were homozygous variant [*3/*3 genotype]) only at the highest dose administered (450 versus 150 or 300 mg).

When CYP3A4 drug- metabolizing capability has become saturated, individuals that express CYP3A5 may metabolize the compound more quickly because of the additional activity of a second major CYP3A enzyme. The present study confirms the association between CYP3A4*1B and prostate cancer occurrence and severity. A novel aspect of this report is that CYP3A43 is also associated with prostate cancer, particularly in the context of family history-positive disease. CYP3A4 is expressed preferentially in the prostate and is involved in testosterone metabolism. CYP3A43 is alternatively spliced and can create mRNA hybrids with CYP3A4.

This evidence for a biological interaction between CYP3A4 and CYP3A43, in addition to their overlapping substrate specificity for testosterone is of potential relevance to the observation made here of interactions between CYP3A4 and CYP3A43. In general, the results showing disease associations with CYP3A4 and CYP3A43 are consistent with knowledge of gene and allele function in these genes as declared by several researches. CYP3A4 and CYP3A43 are involved in the metabolic deactivation (hydroxylation) of testosterone. CYP3A43 is preferentially expressed in the prostate. However, the function of CYP3A4*1B has been controversial.

In addition to epidemiologic evidence that CYP3A4*1B is associated with prostate cancer, the basic science literature has not consistently supported a functionally significant effect. A number of authors have studied the relationship of CYP3A4 expression or function of CYP3A4*1B. Most of the authors concluded that no biologically meaningful effects existed given the small magnitude of effects that were observed. However, almost all studies have reported consistent eleva- tions in expression associated with CYP3A4*1B in the range of 20 –200% increase over the consensus CYP3A4*1A.

Finally, I also report significant differences in haplotype frequency distributions by race and case-control status. The observation that the combined CYP3A4-CYP3A5-CYP3A43 haplotype may contain additional information about risk prediction beyond that of CYP3A4 genotypes alone suggests that other genes in this region may also be involved in the etiology of prostate cancer or that the consideration of haplotypes in this region provides improved statistical information for studies evaluating prostate cancer risk and progression.

Further continuation of my study includes Xenobiotics, like anticancer drugs such as docetaxel, bind to steroid and xenobiotic receptor. Ligand-activated steroid and xenobiotic receptor forms heterodimer with retinoid X receptor and binds to the promoter region of the CYP3A4 gene and activates its transcription. Recent studies showed that coregulators, including silencing mediator for retinoid and thyroid receptor and steroid receptor coactivator-1, mediated basal and xenobiotic-induced transcriptional activity of CYP3A4.

The investigators found that the antifungal agent ketoconazole inhibited corticosterone-induced CYP3A4 transcriptional activity by interacting with these coregulators. Ritonavir may block docetaxel-induced expression of CYP3A4 by also affecting these coregulators. Further studies clearly will be needed to elucidate molecular mechanism by which ritonavir inhibits docetaxel-induced expression of CYP3A4. Moreover Interindividual variability in CYP3A4 expression is a major confounding factor for effective cancer treatment and methods to predict CYP3A4-mediated drug clearance may have clinical utility in this setting.

Although acute inflammation has long been recognised to repress drug metabolism, it is now becoming apparent that cancer patients exhibiting clinical and laboratory features of an inflammatory response have reduced expression of CYP3A4 and possibly other genes relevant to anticancer drug disposition. Cytochrome P450 3A4 (CYP3A4) is the major xenobiotic metabolizing enzyme in humans. A broad specificity coupled with high levels of expression in the liver means it is responsible for the metabolism of more than half of all prescribed drugs (Guengerich,1997).

When patients receive several medications concurrently, unwanted and life-threatening effects can result from the competition for the same drug-metabolizing enzyme affecting the blood levels of the competing drugs. Cancer patients would seem to be significantly at risk in this respect, because CYP3A4 metabolizes a large number of anticancer drugs and patients are generally prescribed other medications to relieve symptoms (e. g. , analgesics) and side effects (e. g. , antiemetics and antidiarrheals) and to treat comorbidities.

The anti- cancer drugs metabolized by CYP3A4 include docetaxel (Marre et al. 1996), cyclophosphamide (Chang et al. , 1993), ifosfamide (Walker et al. , 1994), etoposide (Kawashiro et al. , 1998), tamoxifen (Crewe et al. , 1997), irinotecan (Santos et al. , 2000), vinblastine (Zhou-Pan et al. , 1993), and vinorelbine (Kajita et al. , 2000). Although there is a marked interindividual variation of pharmacokinetic parameters be-tween patients (Evans and Relling, 1999), and such variation in patient response is often attributed to polymorphism in P450 genes, CYP3A4 is an exception because only a small percentage of the variation in activity can be attributed to genotype (Lamba et al. 2002a,b). Interactions with comedicated compounds are therefore likely to be particularly important in explaining variations in anticancer drug pharmacokinetics and side effects. If a patient experiences significant toxicity during chemotherapy, the clinician will usually reduce the dose of the cytotoxic drug, reducing the anticancer effect. A more appropriate action might be to substitute a different comedication that will not interact with the therapy and so maintain dose intensity of the cytotoxic drug.

Thus, identifying potential drug-drug interactions involving CYP3A4 is important for improving the treatment of cancer. The development of methods to predict such interactions could lead to the administration of more effective, less toxic drug regimes. Hence the next objective relating the cancer study will comprise of

1. To review the relevance of CYP3A4 variability to drug metabolism in the setting of cancer and to understand how inflammation associated with malignancy contributes to both this variability and to adverse treatment outcomes.
2. To examine the relationship between tumour-induced inflammation and repression of CYP3A4 and to explore methods of dosing of anticancer drugs in the setting of advanced cancer. In conclusion, the present study confirms the association of CYP3A4*1B and prostate cancer occurrence and severity, suggests a role for CYP3A433 in prostate cancer etiology, and further elucidate the relationships of multiple genotypes and haplotypes at the CYP3A locus with prostate cancer etiology.

Combined with information about the function of these genes, there is growing evidence that one or more of the genes in the CYP3A locus are involved in prostate cancer etiology. The most important and best characterized enzyme of the CYP3A subfamily, CYP3A4, metabolizes many essential drugs. As discussed above, the CYP3A subfamily plays a role in the metabolism of several anticancer agents. It should, however, be emphasized that the metabolism of many essential anticancer agents remains poorly characterized (mainly due to analytical difficulties) and not all P450 enzymes participating in their metabolism have been identified.

Therefore, it is usually not known (with the possible exception of ifosfamide and taxol) to which extent CYP3A enzymes contribute to the overall metabolism of specific anticancer agents. However, the role of CYP3A4 may be crucial in many cases since it is the most abundant P450 enzyme in human liver and it is also inducible. Since many inhibitors and inducers of CYP3A are widely used in clinical practice, the potential for interactions between these agents and anticancer drugs is considerable.

Furthermore, if anticancer agents that are substrates for CYP3A are used together in combination chemotherapy, the efficacy and toxicity of one or more of the components (or any other concomitantly used CYP3A substrate) may increase as a result of competitive inhibition of metabolism. It should also be recognized that many anticancer agents have active metabolites which, depending on their potency and pharmacokinetics, may contribute to the clinical response.

Inhibition of the metabolism of the (active) parent drug might result in reduced production of an essential active metabolite, and the effects of the parent drug might not be enhanced as much as the increased plasma concentrations would suggest. Therefore, it is difficult to evaluate the clinical significance of pharmacokinetic interactions without pharmacodynamic data. In the light of the role of the CYP3A subfamily in the metabolism of several anticancer agents and the effects of P-glycoprotein inhibitors on their pharmacokinetics, appropriate caution should be exercised when combining other drugs with cancer chemotherapy.

Interestingly, many CYP3A4 substrates are P-glycoprotein inhibitors. More clinically important interactions between anticancer drugs and CYP3A inhibitors as well as P-glycoprotein inhibitors are likely to emerge, and further study is required in this field.

References

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3. Hamzeiy H, Bombail V, Plant N, Gibson G, Goldfarb P. Transcriptional regulation of cytochrome P4503A4 gene expression: effects of inherited mutations in the 5-clinical presentation of prostate tumors by a novel genetic variant in CYP3A4.
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6. The CYP3A41B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer.
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9. Channa Keshava, Erin C. McCanlies, and Ainsley Weston CYP3A4 Polymorphisms—Potential Risk Factors for Breast and Prostate Cancer: A HuGE Review
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