Bioactivation of chloroform in hepatic microsomes from rodent strains susceptible or resistant to CHCl3 carcinogenicity.
The dependence of adduct formation on oxygen concentration and glutathione (GSH) presence was used to characterize the bioactivation of chloroform in hepatic microsomes of Sprague-Dawley and Osborne-Mendel rats and B6C3F1 and C57Bl/6J mice. Both oxidative and reductive pathways were present in all the animals tested. Oxidative activation, very sensitive to oxygen withdrawal, was the major pathway responsible for the covalent binding to microsomal proteins and lipids at 0.1 mM CHCl3. The relative contribution of either pathway to the covalent binding to microsomal lipids at 5 mM CHCl3 was dependent on the oxygen concentration. At 1% pO2, i.e., in the range of the hepatic physiological oxygenation level, B6C3F1 mouse hepatic microsomes showed an oxidative activation distinctly higher than that of hepatic microsomes of other rodents; on the other hand, reductive activation was present only in B6C3F1 mouse and Osborne-Mendel rat liver microsomes. The reductive intermediates were the only contributors to the covalent binding of CHCl3 equivalents to lipids in the presence of GSH; indeed the reactive intermediates produced by the oxidative pathway were fully scavenged by this compound. These results are discussed with respect to the species specificity of CHCl3 hepatocarcinogenesis.
Testai
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Istituto Superiore di Sanità, Comparative Toxicology and Ecotoxicology Department, Rome, Italy.
Gemma
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Vittozzi
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D000818:Animals; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D002725:Chloroform / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D004247:DNA / Q000378:metabolism; D007680:Kidney Neoplasms / Q000139:chemically induced; D050356:Lipid Metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012377:Rodentia / Q000502:physiology*; D013045:Species Specificity
D002250:Carbon Radioisotopes; D002273:Carcinogens; D011506:Proteins; D002725:Chloroform; D004247:DNA