Data for this review were identified by searches in PubMed and references cited in relevant articles. Search terms included: “pharmacogenetics”, “pharmacogenomics”, “drug metabolism”, “oncology”, “chemotherapy”, and “cytochrome P450”. Only papers published in English were included.
ReviewModulation of cytochrome P450 activity: implications for cancer therapy
Introduction
Anticancer agents have a wide variation between individuals in response, owing partly to pharmacokinetic variability. The most common strategy used to restrict pharmacokinetic variability is to relate doses of drugs to the patient's body surface area (BSA). This approach is based on the assumption that each individual is capable of metabolising drugs with the same efficacy. However, BSA-based dosing strategies do not reduce variability between individuals in the pharmacokinetics of most chemotherapeutic agents.1 Therefore, other factors must contribute to drug disposition as well as therapeutic efficacy and toxic effects.
One of the sources of variation in drug effects is differences between individuals in inherited elements of drug response.2 Genetics is estimated to account for 20–95% of variability in therapeutic response and toxic effects. Research in pharmacogenomics aims to elucidate the genomic determinants of drug disposition and effect.3 Genetics affects various factors influencing drug disposition, including drug absorption, metabolism, distribution, and excretion.3 Several reviews on pharmacogenomics and cancer therapy have been published, but have focused mostly on genetic variability in phase II reaction enzymes such as UDP glucuronosyltransferase, N-acetyltransferases, and thiopurine methyltransferase.2 Here, we focus on drug metabolism, specifically the role of metabolism mediated by cytochrome P450s, on cancer therapy and the endogenous and exogenous factors that influence the activity of these enzymes.
The cytochrome P450 enzymes catalyse the oxidation of many structurally unrelated compounds of endogenous and exogenous origin. They also have important roles in the extent and duration of drug effects, by catabolising drugs to inactive metabolites or by bioactivating prodrugs to their active forms. Several anticancer agents are metabolised by cytochrome P450s (table).
Section snippets
Bioactivation and resistance
The most important site of metabolism mediated by cytochrome P450 is the liver, where the enzymes are ubiquitously expressed (figure 1). For CYP3A-mediated metabolism of drugs administered orally, the gastrointestinal tract is also potentially important. Enzymatic biotransformation within various other organs, such as the brain, lung, and kidneys, has been documented in experimental systems, but evidence of clinically relevant metabolism at these sites is lacking. There is also evidence that
Factors affecting activity of cytochrome P450s
Different factors can contribute to the variable activity of cytochrome P450s. The expression of these enzymes can be affected by endogenous factors such as an individual's age, sex, concomitant disease (such as cancer, hepatic dysfunction, or renal impairment), and genetic polymorphisms.8, 9, 10, 11
Anticancer agents metabolised by cytochrome P450
Experiments with one or more of the various liver preparations available or with recombinant cytochrome P450 isoforms can identify the specific enzymes involved in the metabolism of each of the anticancer agents that are substrates for the enzyme system (table). In general, knowledge of which isoforms have roles in the transformation of an anticancer agent facilitates the prediction of interactions with other drugs. However, these in-vitro systems have limitations.32
The clinical importance of
Conclusions
A most important difficulty in cancer pharmacology is the prediction of outcome of therapy, in terms of both tumour response and toxic effects. In general, identification of specific factors that might affect cytochrome P450 activity, the pharmacokinetics, and the pharmacodynamic profile of drugs in healthy individuals is difficult. Measurement of cytochrome P450 activity in individual patients with cancer is even more complex, given their heterogeneous backgrounds and the complex physiological
Search strategy and selection criteria
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