The role of cytochrome P450 in cytotoxic bioactivation: future therapeutic directions

Abstract

The cytochrome P450s are an essential group of enzymes involved in metabolism of drugs, foreign chemicals, arachidonic acid, cholesterol, steroids and other important lipids. The cytochrome P450 enzyme system is responsible for much of the phase I metabolism of chemotherapeutic agents. At the simplest level the detoxification properties of the cytochrome P450s are used to help clear a cytotoxic before it results in serious irreversible toxicity to the patient while at other levels the cytochrome P450s are involved to varying extents in drug bioactivation. This metabolism primarily occurs in organs and tissues of the body known to express cytochrome P450 ubiquitously (i.e. liver and gastrointestinal tract), but there is also evidence to suggest that it occurs within the tumor microenvironment due to localized, tumor specific expression of certain P450 isoforms. Several of today's currently prescribed cytotoxics (e.g. cyclophosphamide and tamoxifen) undergo systematic bioactivation by cytochrome P450, which often results in toxicity to the patient. The realization that many tumors have differential cytochrome P450 expression when compared to the corresponding normal tissue has allowed the rational design of the next generation of cytotoxic around cytochrome P450 enzymology. Several new agents now entering clinical trials (e.g. Phortress and AQ4N) are specifically designed to exploit tumor cytochrome P450, resulting in local bioactivation of the cytotoxic at the tumor site. Specific activation of pro-drugs by isoforms whose expression or particular catalytic activity is limited to cancer cells offers the possibility of truly targeted chemotherapy with minimized systemic toxicity.