Pharmacogenomics of Cytochrome P450 Enzymes in Tumours

Diane      Downie; Patrick   H.   Rooney; Morag   C.E.   McFadyen; Graeme   I.   Murray

Abstract

The field of pharmacogenomics is continuously progressing with the development and availability of molecular biotechnologies such as protein and DNA chips. These applications are pushing forward the frontiers towards individualised medicines and advanced predictions of an individuals predisposition to diseases such as asthma, cardiovascular disease and cancer. The cytochrome P450s are an essential group of enzymes involved in metabolism of many currently administered drugs as well as foreign compounds and endogenous substrates. Inter-individual variation in response to cancer chemotherapy is often attributed to genetic alterations in this particular group of drug metabolising enzymes. Such alterations can impact on the pharmacokinetics and pharmacodynamics of anti-cancer drugs, especially those drugs with a narrow therapeutic index. The identification of variations is therefore, key in the areas of drug selection and dosage. Polymorphisms have been identified in many P450s including the CYP2C and CYP3A families, as well as CYP2D6 and CYP1B1. Polymorphisms in CYP2C and CYP3A family members have demonstrated altered cytotoxic drug potential while polymorphisms in CYP1B1 are considered potentially important in the etiology of a range of human cancers. However, the functional significance of P450 variants in tumours is largely unknown. Importantly, the identification of differential cytochrome P450 expression between tumour and corresponding normal tissue are key to the development of novel drugs and therapeutic strategies that can utilise the overexpression of these enzymes to their benefit. It is for these reasons that variants in the cytochrome P450 multigene family have become the focus of current research in this area.

Keywords: pharmacogenomics, cytochrome p450, cyp1b1, polymorphism, anticancer agent, neoplasm

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