Invited Speaker

Polymorphic Cytochrome P450 Enzymes: Challenges for Anticancer Drug Discovery and Development
Emel Arinç
Turkey

Currently, fifty-seven functional cytochromes (CYPs) in 18 families have been identified in humans. CYPs in families 1-4 are responsible for about 75-80% of all phase-I dependent metabolism of clinically used drugs and of thousands of xenobiotics. CYPs also play a crucial role in the synthesis and metabolism of a variety of physiologically active compounds including steroid hormones, bile acids, vitamine D, thromboxane and prostaglandins. CYPs have been shown to have an increasingly important role during drug design and development. Inhibitors of specific CYPs are used to design target-specific drugs. CYP19A1, the steroid aromatase, catalyzes synthesis of estrogens from androgens by monooxygenation reactions. Following the discovery that excess estrogen supports tumor growth in the majority of the breast cancer patients, inhibition of estrogen synthesis and/or estrogen function by antiestrogens is appeared feasible for anticancer drug design. Rational design and synthesis of second and third generation of aromatase inhibitors such as fadrozole, anastrozole, and letrozole are used as potentially useful drugs for the control of estrogen dependent mammary tumors. CYP17A1 catalyzes androgen production. Since excess amounts of androgens can induce development of prostate cancer, much effort is focused into the design and synthesis of CYP17A1 inhibitors with high affinity and selectivity towards CYP17A1. It is also well known that vitamin D and its metabolites have protective effect against cancers. 1, 25-Dihydroxyvitamin D3,(1,25-D3), the biologically most active metabolite of Vitamin D3, is used in the therapy of malignant diseases such as prostate cancer. Since this antitumorigenic agent, 1,25-D3, is inactivated by CYP24 (24-hydroxylase), inhibitors of CYP24 may represent a novel class of anticancer drugs. On the other hand, the major concern of the drug industry and medical sciences today is the extensive interindividual variation in drug metabolism which results in therapeutic failure, unpredictable drug response, and toxicity. The variation observed in drug metabolism is mainly due to induction or inhibition of these enzymes resulting from multiple drug therapies or environmental factors and genetic polymorphisms. Drug-drug interactions during multiple drug therapy result in competitive inhibition of enzymes responsible for elimination of the drug. Such an interaction leads to increased plasma levels of drugs with the potential for concomitant toxic effects. Induction of CYPs by drugs lowers the plasma levels, and pharmacological response is reduced. Some drugs or chemicals induce CYP1A by 10 to 100 fold, which converts pre-carcinogens to their carcinogenic metabolites. Scientists are now regarding the potential of a new drug candidate to induce CYP1A as an indicator of likely carcinogenicity and drop the candidate from further drug development studies. In human liver, drugs are mainly catalyzed by CYP1A2, CYP2A6, CYP2B6, CYP2C9/19, CYP2E1, CYP2D6 and CYP3A4. Some of the CYPs have been shown to be highly polymorphic such as CYP2D6 and CYP2C9/19. As a result of ultrarapid metabolism of a drug, the concentration of the drug in blood decreases resulting in therapeutic failure. Increased concentration of a drug observed in slow metabolizers results in high pharmacological action and toxic effect. Drugs that are selectively metabolized by highly polymorphic enzymes create a problem for the drug industry, so they are often dropped early in drug screening. In addition, relative distribution of variant alleles for the drug metabolizing enzymes differs markedly between ethnic groups, which make drug industry’s work even more difficult and complicated. Thus, it is expected to have fewer problems with polymorphic enzymes during drug therapy in the future.

References

1. Ortiz de Montellano, P R (2005). Cytochrome P450: structure, mechanism, and biochemistry (3rd ed.). New York: Kluwer Academic/Plenum Publisher

2. Lu,AYH in: E. Arinç, J. B. Schenkman, E. Hodgson (eds), Molecular Aspects of Oxidative Drug Metabolizing Enzymes: Their Significance in Environmental Toxicology, Chemical Carcinogenesis and Health, Springer-Verlag, Heidelberg, 1995, pp. 503-513.

3. Ulusoy G., Adali O., Tumer T. B., Sahin G., Gozdasoglu S.,and Arinç, E.: Oncology, 72(1-2), 125-131, 2007.

4. Tumer T. B., Ulusoy G, Adali O., Sahin, G., Gozdasoglu, S., and Arinç, E.: American Journal of Hematology, 82(10), 906-910, 2007.