Effect of senescence on the bioactivation of aliphatic halides

Since the toxicity of xenobiotics is often related to their metabolism, this study was concerned with the relationship between aging and the bioactivation and covalent binding of certain aliphatic halides to microsomal protein and lipid. Hepatic microsomes were isolated from control and phenobarbital induced young (4 mo), adult (11 mo) and senescent (27 mo) Fischer 344 rats. Bioactivation and subsequent covalent binding were studied with 14C-labeled 1,2-dibromoethane, carbon tetrachloride, trichloroethylene, and 1, 1, 2-trichloroethane. With control rats, levels of binding increased slightly between 4 and 11 mo; however the values decreased 50-75% in the 27 mo group compared to the 11 mo group. No significant differences were noted between phenobarbital induced groups with regards to bioactivation of the aliphatic halides and their covalent binding to proteins and lipids. As an explanation for the decreased bioactivation ability in the senescent rats, they were also found to have significantly less hepatic cytochrome P-450 (-35%), NADPH cytochrome C reductase (-31%), and ethyl-morphine N-demethylase activity (-43%) when compared to the 11 mo age group. These differences were reduced when comparisons were made between the various age groups of phenobarbital induced animals. This suppression may indicate a decreased potential for the expression of toxicities requiring bioactivation.