Bioactivation, toxicokinetics and acute effects of chloroform in Fisher 344 and Osborne Mendel male rats.
Chloroform has been regarded as a renal carcinogen, based on results obtained with Osborne Mendel (OM) rats. Fisher 344 (F344) rats, considered representative of OM rats on the basis of comparable acute toxic effects, have been used in most of the studies aimed to elucidate the mechanisms of kidney tumour induction. In the present work, in vitro and in vivo chloroform bioactivation in the liver and kidney of F344 and OM rats has been reported, as well as additional toxicokinetics and acute toxicity information. Complete similarity of chloroform metabolism and toxicokinetics was evidenced in the two rat strains. Chloroform metabolism was fully saturated at the OM rat bioassay doses (90-180 mg kg(-1) body wt.), working at a maximal rate of 40-50 micro mol (14)CO(2) expired kg(-1) h(-1). No acute hepatotoxicity, nephrotoxicity or consequent cell proliferation was evidenced at 180 mg kg(-1) body wt. chloroform. In the rat liver, phosgene was confirmed as the major metabolite. Renal microsomes from both F344 and OM rats in vitro were unable to produce any oxidative metabolite; at variance, adducts due to oxidative and reductive metabolites were detected in vivo. Our results indicated the presence in the rat kidney of electrophilic metabolites other than phosgene, representing either oxidative metabolites formed elsewhere and sufficiently stable to be transported to the kidney or electrophilic metabolites secondary to the formation of reductive radicals. Therefore, the rat kidney represents a suitable model to study the toxicological effects, including genotoxicity, of chloroform metabolites in the absence of cytotoxic effects produced by phosgene formed in situ.
Gemma
Simonetta
S
Biochemical Toxicology Unit, Comparative Toxicology and Ecotoxicology Laboratory, Istituto Superiore di Sanità, Rome, Italy.
Testai
Emanuela
E
Chieco
Pasquale
P
Vittozzi
Luciano
L
D000818:Animals; D002725:Chloroform / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012997:Solvents / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D013045:Species Specificity; D014018:Tissue Distribution
D012997:Solvents; D002725:Chloroform