Abstract
Biphenyl metabolism has been extensively studied in isolated viable adult rat hepatocytes in suspension with regard to both phase I and phase II reactions. A wide range of primary and secondary metabolites are produced by these cells, which closely reflects the situation appertaining vivo. Using biphenyl, and the three primary metabolites, 2-, 3- and 4-hydxoxybiphenyl, assessment of toxicity due to the substrate, primary or secondary metabolites, examination of the relationship between phase I and phase II metabolism, and the effect of inducers and inhibitors on the total metabolic profile has been made. Possible rate limiting phenomena operating in the intact cell that affect the rate of xenobiotic metabolism have also been studied. With this insight into the isolated hepatocytes metabolic capabilities, particularly with respect to xenobiotic metabolism, isolated adult rat hepatocytes in suspension and primary maintenance Culture were then used as to vitro model systems for the assessment of xenobiotic-induced toxicity. Using a mixed liver cell approach, the fibroblast cytotoxicity (as measured by inhibition of cell growth) of a number of xenobiotics is shown to be fully expressed only when metabolised to their 'active' species by the hepatocytes to vitro, closely reflecting the situation known to occur to vivo. The versatility and general applicability of such a mixed-cell approach, to in vitro toxicity and carcinogenicity assessment of xenobiotics is discussed. In order to decide whether hepatocytes model systems could be used to assess a xenobiotics hepatotoxic potential, the changes in viability and functional capabilities of cultured hepatocytes were monitored after exposure to known in vivo hepatotoxic agents. Results presented here indicate that xenobiotics that are hepatotoxic in vivo are also hepatotoxic vitro, though whether by a similar mechanism is as yet unclear. The advantages and limitations to the use of such in vitro hepatocyte model systems for the assessment of xenobiotic-induced toxicity in the light of the wide range and variety of other in vitro models that are currently being used are discussed.