PROBLEMS IN USING ISOLATED AND CULTURED-HEPATOCYTES FOR XENOBIOTIC METABOLISM/METABOLISM-BASED TOXICITY TESTING--SOLUTIONS

Isolated and cultured hepatocytes would seem to be an ideal model for the study of hepatic xenobiotic metabolism and metabolism-based hepatotoxicity. However, a serious drawback with this system of testing is the loss of xenobiotic-metabolizing capacity in a reaction-dependent manner when the cells are kept in culture for any extended period. Many ways of modifying culture methods to overcome this problem have been investigated, for example the use of different culture media, culture media additions (e.g. hormones, serum, minerals, vitamins, and xenobiotics such as metyrapone and dimethyl sulfoxide), culturing on a substratum of components of the extracellular matrix or on microcarriers, and co-culturing with other hepatic or with non-hepatic cells. However, these methods have achieved only limited success, with only some enzyme activities being preserved or many activities being preserved to only a limited degree. Furthermore, the variations between the methods used in hepatocyte isolation and culture preclude interlaboratory correlations of results. It is likely that a combination of the methods that have been investigated will yield a workable and reliable culture method to maintain xenobiotic metabolizing capacity in isolated hepatocytes, and co-ordination of research in this area should be promoted to achieve this outcome.