EFFECT OF PHENOBARBITAL AND MIREX PRETREATMENTS ON CCL4, AUTOPROTECTION

Male Sprague-Dawley rats maintained on either normal diet (N) or on a diet containing phenobarbital (PB; 225 ppm) or mirex (M; 10 ppm) for 1 5 days received either corn oil or 1 single administration of a protec tive dose of CCl4 (0.3 ml/kg, po) on day 16. At 24, 48, 72, 96, or 144 hr after the protective dose, a high dose of CCl4 (5 ml/kg, po) was a dministered to rats of all the groups, and they were observed for 14-d ay lethality. In a second experiment, in rats maintained on N, PB, or M diet, liver microsomal cytochromes P-450, aminopyrine demethylase, a nd aniline hydroxylase were measured at various time points after the administration of the protective dose of CCl4. Serum aspartate transam inase, alanine transaminase, and sorbitol dehydrogenase elevations and histopathological changes observed under a light microscope were used as toxic end points to assess hepatotoxicity. Autoprotection was 100% when the high dose was given at 24 hr after the protective dose in N rats, whereas it was only 55% in PB- or M-pretreated rats. For later t ime points of 48, 72, and 96 hr, autoprotection was only around 50% in N rats, whereas it was almost 100% in PB- and M-pretreated rats. When the high dose was administered at 144 hr after the protective dose, a utoprotection further declined to 25% in N rats and to 75% in M-treate d rats, but it remained at 100% in PB-treated rats. The liver microsom al cytochromes P-450, aminopyrine demethylase, and aniline hydroxylase were induced in rats after the dietary treatment with PB or M when co mpared to the rats on N diet. However, after administration of the pro tective dose of CCl4 to these rats, these enzyme activities were decre ased in all the groups at 24 hr after the protective dose, persisted a t a low level even at the 72-hr time point, and then slowly recovered to normal by 120 hr. Liver injury was evident by serum enzyme elevatio ns and histopathological changes in all the groups at 24 hr after the protective dose, but the injury was progressive in PB- and M-treated r ats with maximum injury at 48 hr, injury in PB-treated rats being grea ter than that in M-treated rats. The livers recovered completely in al l the groups by 120 hr as revealed by serum enzymes and liver histolog y. The levels of microsomal enzymes at various time points after the p rotective dose in N, PB, and M treatment groups correlate neither with liver toxicity nor with animal survival after the administration of t he large dose of CCl4. Therefore, a postponement of the hepatocellular regeneration stimulated by the protective dose of CCl4 caused by prio r exposure to PB and M, as reported earlier, appears to play a role in the correspondingly postponed maximal expression of CCl4 autoprotecti on. Furthermore, the prolongation of autoprotection by M and even grea ter effect by PB appears to be related to the greater stimulation of h epatocellular proliferation and augmented tissue repair processes attr ibutable to the protective dose of CCl4 reported previously.