ABsTFZACXThe destruction of liver microsomal cytochromes P4so by a previously administered low dose of CCl, has been widely accepted as the mechanism of CCl, autoprotection. However, circumstantial evidence suggests that this mechanism cannot completely explain the phenomenon of autoprotection. The protective effect of a low dose of CCl, (0.3 mVkg, PO) on the lethal effect of a subsequently administered high dose (5 mUkg, PO) was established in male Sprague Dawley rats. The protective dose permitted 100% survival, whereas only 15% survival was observed without it. Hepatotoxicity, measured by serum enzyme elevations (aspartate transaminase, alanine transaminase, and sorbitol dehydrogenase) and histopathological changes 24 hr after the treatment with high dose, was similar in both the groups, even though the protective dose had significantly decreased liver microsomal cytochromes P,,, (to 62% of normal) and associated enzymes, aminopyrine demethylase and aniline hydroxylase. Rats pretreated with CoCl, to decrease hepatic microsomal cytochrome P450 to 44% of normal levels did not show a significant protection from the hepatotoxicity of high dose of CCI,. Previous studies have established that hepatocellular regeneration is stimulated within 6 hr after the administration of a low dose of CCI,. Based on this observation, a premise that autoprotection results from augmented recovery from injury rather than decreased injury appears likely. Hence, the role of hepatocellular regeneration was evaluated by following 'H-thymidine incorporation in hepatocellular nuclear DNA, labelling index by autoradiography, and by morphometric estimation of mitotic index. After administration of the protective dose of CCl,, stimulated nuclear DNA synthesis measured by 3H-thymidine incorporation into nuclear DNA was increased and this remained high even after subsequent administration of high dose of CCl,. Forty-eight hr after the administration of a lethal dose of CCl, alone (5 mVkg, po), labelling index was slightly increased, but mitotic index was not increased. In the surviving rats (15%), both labelling index and mitotic index were significantly elevated after an additional 24 hr. In rats receiving the protective dose, a significantly greater elevation of labelling index as well as mitotic index occurred 48 hr after the administration of the same lethal dose of CCl,. These results suggest that hepatocellular regeneration stimulated by the protective dose, as a biological response recruited to overcome the accompanying limited injury, may augment and sustain tissue repair processes to permit tissue restoration even after the massive liver injury elicited by the subsequent large dose of CCI,.

The purpose of this study was twofold: 1) to characterize the profile of colonic peptide YY (PYY) gene expression in rats and 2) to examine for potential trophic effects of PYY on the intestine in rats and mice. Expression of PYY mRNA (analyzed by Northern blotting and in situ hybridization) and PYY (analyzed by high-performance liquid chromatography and radioimmunoassay) was detected initially at day 17 of gestation in colonic extracts of Sprague-Dawley and Fischer rats. Expression of colonic PYY mRNA increased until 7 days of age and remained at its highest level (approximately twofold greater than the adult level) through the end of the nursing period. After weaning (21 days of age), PYY mRNA levels declined quickly to adult levels. Colonic PYY concentrations followed, in a coordinated manner, with some temporal delay after birth, the increase and decrease of its mRNA. Administration of PYY increased the weight and DNA content of the duodenum significantly in nursing rats and adult mice. In mice, PYY treatment also increased weight and DNA content of the ileum and colon. The trophic effects of PYY were dose related, peptide specific, and independent of species and sex. From these findings, we hypothesize that PYY plays an important role in intestinal development and dietary adaptation.

Autoprotection is a phenomenon whereby prior exposure to a small dose of a chemical results in protection against a subsequently administered lethal dose of the same compound. While CCl4 autoprotection has been studied the most, it has also been demonstrated for other chemicals. Recent studies indicate that the prevailing concept of decreased bioactivation of the normally lethal dose of CCl4 owing to decreased hepatic microsomal cytochrome P-450 content cannot be supported by direct end points of liver injury such as necrosis. These findings suggest a pivotal role for hepatocellular division and tissue healing processes stimulated by the protective dose in the mechanism of autoprotection. Augmentation of hepatocellular regeneration and tissue repair, stimulated by the protective dose, appears to permit timely recovery and restoration of hepatic structure and function. In the absence of the protective dose, hepatocellular division is substantially deficient and it occurs too late to tip the delicate balance between recovery from injury and progression of massive injury in favor of recovery. Abolition of autoprotection by colchicine antimitosis, under conditions where metabolism and disposition of CCl4 are not altered, is supportive of this concept. Selective colchicine antimitotic suppression of the early phase of hepatocellular division and tissue repair induced by a low dose of CCl4 results in progression of toxic liver injury, leading to hepatic failure and mortality. Studies have shown that pretreatment with phenobarbital results in postponed low-dose CCl4-stimulated cell division by 24 hours, which accordingly postpones the optimal autoprotection.(ABSTRACT TRUNCATED AT 250 WORDS)

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 15 days received either corn oil or 1 single administration of a protective dose of CCI, (0.3 mVkg, PO) on day 16. At 24, 48, 72,96, or 144 hr after the protective dose, a high dose of CCI, (5 mVkg, PO) was administered to rats of all the groups, and they were observed for 14-day lethality. In a second experiment, in rats maintained on N, PB, or M diet, liver microsomal cytochromes P-450, aminopyrine demethylase, and aniline hydroxylase were measured at various time points after the administration of the protective dose of CCl,. Serum aspartate transaminase, 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 time 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, autoprotection further declined to 25% in N rats and to 75% in M-treated rats, but it remained at 100% in PB-treated rats. The liver microsomal cytochromes P-450, aminopyrine demethylase, and aniline hydroxylase were induced in rats after the dietary treatment with PB or M when compared to the rats on N diet. However, after administration of the protective dose of CCl, to these rats, these enzyme activities were decreased in all the groups at 24 hr after the protective dose, persisted at 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 elevations and histopathological changes in all the groups at 24 hr after the protective dose, but the injury was progressive in PB-and M-treated rats with maximum injury at 48 hr, injury in PB-treated rats being greater than that in M-treated rats. The livers recovered completely in all the groups by 120 hr as revealed by serum enzymes and liver histology. The levels of microsomal enzymes at various time points after the protective dose in N, PB, and M treatment groups correlate neither with liver toxicity nor with animal survival after the administration of the large dose of CCl,. Therefore, a postponement of the hepatocellular regeneration stimulated by the protective dose of CCl, caused by prior exposure to PB and M, as reported earlier, appears to play a role in the correspondingly postponed maximal expression of CCl, autoprotection. Furthermore, the prolongation ofautoprotection by M and even greater effect by PB appears to be related to the greater stimulation of hepatocellular proliferation and augmented tissue repair processes attributable to the protective dose of CCl, reported previously.