Species differences in oxidative drug metabolism: some basic considerations.

Abstract

Perhaps one of the single most important developments in the past 20 years in the understanding of chemical toxicity has been the realisation of the importance of metabolic transformation in this process. It is now widely appreciated that the toxic effects of many chemicals is a function of their metabolism rather than the substance itself. Of central interest to the toxicologist therefore is an understanding of the metabolism of a toxic chemical and the significance of this in the toxic process. The metabolic process itself however can be highly variable both between and within animal species. For this reason the toxicologist may have to consider both species and strain differences in metabolism when attempting to extrapolate findings to man in the safety evaluation process. For the past twenty years, work on species differences in metabolism has been largely of a descriptive nature and the cataloguing of differences. However, developments in the last few years in the understanding of the genetic diversity of species, including man, in terms of biotransformation and the nature and substrate preferences of the various multiple forms of the drug-metabolizing enzymes now give a better insight into the nature of species differences of metabolism. Furthermore, an understanding of this problem tempers expectations in terms of what may be hoped for in the extrapolation from other species. For example, the search for a species that metabolizes like man will be seen to be ill-conceived and ill-advised. The presentation deals with some of the fundamental aspects of species and strain differences in oxidative metabolism in particular and the implications that this has for the toxicologist in the safety evaluation process.