Individuality in cytochrome P450 expression and its association with the nephrotoxic and carcinogenic effects of chemicals

The susceptibility of a tissue to the toxic and/or carcinogenic effects of chemicals is determined by a variety of factors, which include their rate of metabolic activation by the cytochrome P450-dependent monooxygenases. Individual differences in the levels of cytochrome P450 expression would be expected, and are known, to give rise to profound differences in toxicological response. Such effects are almost best exemplified by the sex differences observed in the toxic effects of a variety of nephrotoxins and carcinogens. In recent work, we have shown that in species such as the mouse and rat almost all cytochrome P450 enzymes in the kidney are sexually differentiated. This difference in cytochrome P450 regulation is mediated by testosterone and explains the large differences observed in the metabolic activation, toxicity and carcinogenicity of chloroform and possibly of other compounds such as ochratoxin A. In addition to hormonal or environmental influences on cytochrome P450 expression, genetic factors have also been shown to be important. In man, this is best exemplified by the genetic polymorphism observed in the metabolism of debrisoquine and approximately 25 other drugs. This genetic defect affects approximately 5-10% of the Caucasian population and has been associated with altered susceptibility to cancer. In this presentation, the development of a simple DNA-based assay to identify affected individuals is described. Use of this assay will allow clarification of the reported association of this genetic polymorphism to susceptibility to Balkan nephropathy and cancer.