Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The destruction of liver microsomal cytochromes P450 by a previously administered low dose of CCl4 has been widely accepted as the mechanism of CCl4 autoprotection. However, circumstantial evidence suggests that this mechanism cannot completely explain the phenomenon of autoprotection. The protective effect of a low dose of CCl4 (0.3 ml/kg, po) on the lethal effect of a subsequently administered high dose (5 ml/kg, 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 P450 (to 62% of normal) and associated enzymes, aminopyrine demethylase and aniline hydroxylase. Rats pretreated with CoCl2 to decrease hepatic microsomal cytochrome P450 to 44% of normal levels did not show a significant protection from the hepatotoxicity of high dose of CCl4. Previous studies have established that hepatocellular regeneration is stimulated within 6 hr after the administration of a low dose of CCl4. 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 3H-thymidine incorporation in hepatocellular nuclear DNA, labelling index by autoradiography, and by morphometric estimation of mitotic index. After administration of the protective dose of CCl4, 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 CCl4. Forty-eight hr after the administration of a lethal dose of CCl4 alone (5 ml/kg, 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 CCl4. 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 CC14.
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PMID:Role of hepatocellular regeneration in CCl4 autoprotection. 204 7

The potentiation of CCl4 toxicity by pre-exposure to chlordecone (CD) is well established. Chlordecone-induced metabolism of CCl4 and suppressed hepatocellular repair have been offered as possible mechanisms for this potentiation. Recent work using the partially hepatectomized (PH) rat as a model for an actively regenerating liver has provided supportive evidence for the latter hypothesis. The present study was initiated to determine if metabolism and disposition of 14CC14 is altered in the PH rat, and if this is a contributing factor to the reported protective effect afforded by the PH procedure. Male Sprague-Dawley rats (150-175 g) maintained on dietary CD (10 ppm) for 15 days were partially hepatectomized or sham-operated (SH) on day 15. Another group of CD-pretreated rats received 0.9% CoCl2 (60 mg/kg, sc, qd for 2 days) in lieu of the surgical procedure. On day 16 the rats were challenged with a single dose of CCl4 (100 microL/kg, ip) containing 20 muCi 14CCl4. A radiolabel inventory consisting of exhaled 14CCl4, 14CO2 production, total hepatic 14C, free 14CCl4 and covalently bound 14C was taken over a 6-hr time period. Lipid peroxidation and serum enzyme activities [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] were measured in indices of toxicity. Neither CD pretreatment alone nor CoCl2 treatment alone produced significant alterations in metabolism of low dose (100 microliters/kg) CCl4. No significant difference in 14CCl4 recovery or 14CO2 production was detected for PH versus SH rats. Hepatic 14CCl4-derived 14C (per gram tissue) was greater in PH rats. Values for free 14CCl4, covalently bound 14C, and lipid peroxidation were similar for SH and PH rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Carbon tetrachloride metabolism in partially hepatectomized and sham-operated rats pre-exposed to chlordecone (Kepone). 248 48

Concurrent treatments of cobalt chloride (CoCl2) and phenobarbital (PB), alone or in combination with lithocholic acid (LCA), were administered to rats for 7 days to assess whether or not a hypoactive hypertrophic smooth endoplasmic reticulum (HHSER) could be induced, as well as investigating the potential role of HHSER in the pathogenesis of cholestasis. LCA given alone slightly reduced hepatic triglycerides, significantly elevated plasma triglycerides and decreased microsomal glucose-6-phosphatase (G6P-ase) activity. PB administered alone significantly increased hepatic phospholipids and microsomal protein, phospholipid and cytochrome P-450 contents, as well as microsomal aminopyrine-N-demethylase (APDM-ase) activity. Functional indicators of liver impairment were associated primarily with CoCl2 treatment, whether given alone or in combination with PB + LCA. These signs included significantly reduced hepatic triglycerides, and increased plasma triglycerides associated with enhanced release of hepatic VLDL-triglycerides, as well as significantly decreased microsomal G6P-ase activity and/or reduced APDM-ase activity and cytochrome P-450 content. Elevated plasma bilirubin levels, and aspartate and alanine aminotransferase activities were also evident with concurrent CoCl2 + PB + LCA treatments. Combined CoCl2 + PB treatments, with or without LCA, caused significant increases in microsomal protein and phospholipid, and decreased activity of the rough endoplasmic reticulum (RER) marker G6P-ase, but no changes in cytochrome P-450 levels and no marked alterations in the activity of the SER marker APDM-ase. The data indicated that simultaneous CoCl2 and PB treatments, whether given alone or in combination with LCA, caused a functional impairment of the RER, and did not induce HHSER membranes.
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PMID:Functional responses of the rat hepatic endoplasmic reticulum to treatment proposed as a model for cholestasis. 668 66