CARBON-TETRACHLORIDE HEPATOTOXICITY AS A FUNCTION OF AGE IN FEMALE FISCHER-344 RATS

Severity of liver damage 24 h after intraperitoneal administration of carbon tetrachloride (0.2 ml/kg) was evaluated in female Fischer 344 r ats aged 5, 14 and 28 months, i.e. in young adulthood, middle age and old age. Carbon tetrachloride-induced hepatotoxicity, as judged by the leakage of hepatic enzymes into the bloodstream and the disappearance of hepatic microsomal cytochrome P450, was much less severe in old ra ts than in young-adult rats. For example, serum sorbitol dehydrogenase (SDH) activity following carbon tetrachloride administration was 680 mu mol/min/l in old rats compared with 1710 mu mol/min/l in young-adul t rats, and the loss of hepatic cytochrome P450 was 25% of the total a mount in old rats compared with 50% of the total in young-adult rats. Spin trapping and electron spin resonance (ESR) spectroscopy were util ized to measure the conversion of carbon tetrachloride to trichloromet hyl radicals in vivo. This primary bioactivation step occurred at simi lar rates in female rats aged 5, 14 and 28 months. In addition, the to tal nonheme iron contents in livers of rats in the three age groups we re similar. Thus, the age associated attenuation of carbon tetrachlori de-induced hepatotoxicity was not explained on the basis of decreased bioactivation to reactive species or decreased availability of iron fo r promotion of lipid peroxidation. The results suggest that other fact ors are important determinants of age-associated changes in sensitivit y to toxic chemicals.