Lethal effects of CCl4 and its metabolism by Mongolian gerbils pretreated with chlordecone, phenobarbital, or mirex.
Gerbils are much more sensitive to the hepatotoxic and lethal effects of CCl4 than rats as indicated by 48-hr LD50 values (0.08 vs 2.8 ml/kg). On the other hand, gerbils are refractory to chlordecone (CD) potentiation of CCl4 toxicity. To investigate the possible mechanism underlying the high sensitivity of gerbils to CCl4 lethality, the metabolism of CCl4 was studied in gerbils pretreated with dietary CD, phenobarbital (PB), or mirex (M) at 10, 225, and 10 ppm, respectively. The hepatic content of 14CCl4, the expiration of 14CCl4 and 14CCl4-derived 14CO2, and lipid peroxidation were measured and the results were compared with the previous data for rats. After the 15-day dietary pretreatment, male gerbils (60-80 g) received 14CCl4 (0.08 ml/kg; sp act 0.04 mCi/mmol) ip in corn oil and the radioactivity present in the expired air was collected for 6 hr. More than 80% of the parent compound as represented by the 14C-label in the toluene trap was expired in 6 hr regardless of the pretreatments. Expiration of 14CO2 measured during the 6 hr after 14CCl4 administration in control gerbils was 3.5-fold more than that in rats and was significantly increased in pretreated groups (M greater than PB greater than CD). PB and M pretreatments resulted in a significant increase of 14C-label bound to the nonlipid fraction of the liver as compared with CD-treated or control gerbils. The radiolabel present in the livers of control gerbils was 5-fold higher than that of rats. In vivo lipid peroxidation measured as diene conjugation in lipid extracts from the livers was lower in gerbils than in rats, and none of the pretreatments significantly affected lipid peroxidation. The serum alanine aminotransferase and aspartate aminotransferase were significantly elevated at 6 hr after CCl4 injection in all groups of gerbils. These data indicate that the more extensive metabolism of CCl4, as represented by 14CO2 formation and 14C-label bound to hepatic tissue, in gerbils as compared with rats, may partially explain the high sensitivity of gerbils to CCl4 toxicity. However, the enhanced metabolism of CCl4 found in CD-, PB-, or M-pretreated gerbils did not lead to amplified hepatotoxic and lethal effects of CCl4. The reason gerbils may be refractory to CD amplification of CCl4 injury might be associated with other factors yet to be investigated.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Z W
ZW
Cai
H M
HM
Mehendale
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002245:Carbon Dioxide / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000378:metabolism / Q000633:toxicity*; D007631:Chlordecone / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D005849:Gerbillinae; D007306:Insecticides / Q000494:pharmacology*; D007928:Lethal Dose 50; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000032:analysis / Q000378:metabolism; D008297:Male; D008917:Mirex / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology*
D007306:Insecticides; D002245:Carbon Dioxide; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007631:Chlordecone; D010634:Phenobarbital; D008917:Mirex