Activation systems in tissue culture toxicity studies

Abstract

There is increasing awareness that the toxicity of many xenobiotics is mediated through the production of active metabolites. The enzyme system most involved in the production of active metabolites would appear to be the cytochrome P-450-dependent microsomal mixed function oxidase (MFO) system, although other enzyme systems may be important in particular instances. The routes of metabolic activation invariably occur alongside, or prior to, opposing inactivation pathways and the rate and extent of production of the active metabolite depends upon the balance of activation/inactivation pathways. The main site of activation of xenobiotic nongenetic toxins would appear to be the liver, whether for hepatic or extra-hepatic toxins, but extra-hepatic activation may also be important for certain extra-hepatic toxins. This awareness of the role of metabolic activation has led to the introduction of various activation systems into tissue culture toxicity studies. However, this use of activation systems should be carefully considered in relation to the proposed use of the tissue culture toxicity study. Thus, if it is intended to study organ-specific toxicity using tissue cultures, then it is essential that the cultured cells retain the ability to activate the relevant organ-specific toxins. The activation systems that have been reported include the whole animal, intact liver cells and liver microsomes. Examples are given to illustrate the relative merits of these systems and the different but nevertheless complementary information that can be gained from use of a number of different activation systems.