Association of CYP3A4 in Cancer Occurrence Severity and Drug Metabolism

Topics: Cancer, Cytochrome P450, Oncology Pages: 22 (6955 words) Published: May 7, 2010
Association of CYP3A4 in cancer occurrence severity and drug metabolism


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, CYP3A4*1B). Case studies of Caucasians and of African-Americans have detected associations between CYP3A4*1B and presentation with biologically aggressive disease. It has been postulated that the presence of the CYP3A4*1B 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. 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).


Cytochrome P450 3A4 (abbreviated...
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