Depression of liver microsomal glucose 6-phosphatase activity in carbon tetrachloride-poisoned rats. Potential synergistic effects of lipid peroxidation and of covalent binding of haloalkane-derived free radicals to cellular components in the process.
Depression of liver microsomal glucose-6-phosphatase (G6Pase) activity is a relevant feature of CCl4 poisoning. In vitro studies from several laboratories led to the hypothesis that a CCl4 promoted lipid peroxidation (LP) process is responsible for that effect. In vivo studies from our laboratory with potent antioxidants in dosage regimes inhibiting LP, however, were in contrast with that hypothesis. In this work we studied the potential preventive effects of Pyrazole (Pyr), alpha-tocopherol (alpha T), and 3-amino-1,2,4-triazole (AT) against CCl4-induced depression of G6Pase activity. Pyr decreases the intensity of the covalent binding (CB) of CCl4 reactive metabolites to cellular components but does not inhibit LP in vitro or in vivo. alpha T inhibits LP in vitro and in vivo and AT inhibits both CB and LP. Our present studies give evidence that AT but neither Pyr nor alpha T are able to prevent the CCl4-induced depression of G6Pase activity. Results are compatible with the hypothesis that the cooperation of both factors is critical to explain the observed effects, and suggest that under in vitro experimental conditions used by others the relevance of LP might be artifactually promoted.
González Padrón
A
A
Centro de Investigaciones Toxicológicas (CEITOX) CITEFA/CONICET, Buenos Aires, Argentina.
de Toranzo
E G
EG
Castro
J A
JA
D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005952:Glucose-6-Phosphatase / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014810:Vitamin E / Q000378:metabolism* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011720:Pyrazoles; D014810:Vitamin E; C031280:pyrazole; D002251:Carbon Tetrachloride; D005952:Glucose-6-Phosphatase; D000640:Amitrole