VITAMIN-A MODULATION OF XENOBIOTIC-INDUCED HEPATOTOXICITY IN RODENTS

Vitamin A (V/A, retinol) has been shown to modulate cells of the immun e system. When rats are pretreated with VA (75 mg/kg/day) for 7 days, there is greatly potentiated liver damage upon, subsequent exposure to hepatotoxicants such as CCl4. This potentiated damage can be blocked by superoxide dismutase or catalase, suggesting that reactive oxygen S pecies are playing a major role in the increased liver injury. The stu dies reported here examined VA-induced modulation of CCl4 hepatotoxici ty in different strains of male rats, female rats, and different strai ns of male mice. Also, the role of VA-induced weight loss on potentiat ion of CCl4 injury was investigated. Rats or mice were dosed with VA ( retinol) at 75 mg/kg/day, pc. for 7 days. In an additional VA dose-res ponse study, mice were given VA at 18.8, 37.5, or 75 mg/kg/day, po, fo r 7 days. On day 8 they were given a dose of CCl4 which elicited mild hepatic damage. On day 9 they were necropsied. Male and female Sprague -Dawley rats, and male Fischer-344 and athymic nude rats pretreated wi th VA had an approximately 10-fold increase in liver damage as compare d to vehicle controls. Pretreatment of male Balb/C, C3H/HeJ, Swiss-Web ster, or athymic nude mice resulted in a marked reduction of CCl4-indu ced hepatic damage. In the dose-response study in mice, increasing dos es of VA elicited increasing amounts of protection from CCl4-induced l iver injury. Paired feeding studies revealed that VA-induced weight lo ss (or decreased weight gain) had no effect on subsequent VA-induced p otentiation (rats) or protection (mice) from hepatic damage caused by CCl4. These results indicate that VA-induced potentiation of CCl4 hepa totoxicity is similar in male and female Sprague-Dawley rats and in ma le T-lymphocyte-deficient nude rats. However, in mice, VA pretreatment results in protection from CCl4-induced liver injury. The results als o show that the VA associated weight loss has no effect on modulation of hepatic injury in rats or mice.