In vivo CHCl3 bioactivation, toxicokinetics, toxicity, and induced compensatory cell proliferation in B6C3F1 male mice.
Chloroform carcinogenicity has often been associated with acute tissue damage and consequent compensatory cell proliferation. However, available data do not fully support this hypothesis, and other biological factors may play a role in the tumor induction by chloroform. The purpose of this study was to characterize the in vivo CHCl3 metabolism and the time course of toxic effects and of cell proliferation in the liver and kidney of B6C3F1 male mice dosed i.p. or by gavage with 150 mg CHCl3/kg body wt. Microsomal phospholipid adducts attributed to (14)CHCl3 metabolism by both oxidative and reductive pathways were detected in both liver and kidney. The levels and composition of the adducts were similar in the liver and kidney of treated animals. In the liver, although no necrosis was histologically detectable, a transient cell proliferation was found starting at 24 and peaking at 48 hr post-treatment. Kidney toxicity was evident by biochemical and cytochemical methods at 5 hr after dosing and progressed to severe necrosis at 48 and 96 hr. An intense kidney cell regeneration began 48 hr after CHCl3 treatment, became maximal at 96 hr, and was sustained for at least the following 3 days. These observations raise questions about the purely epigenetic action of chloroform in tumor induction since bioassays have found tumors in liver but not kidneys of CHCl3-treated B6C3F1 mice.
Gemma
S
S
Department of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanità, Rome, Italy.
Faccioli
S
S
Chieco
P
P
Sbraccia
M
M
Testai
E
E
Vittozzi
L
L
D000818:Animals; D001711:Biotransformation; D002245:Carbon Dioxide / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002725:Chloroform / Q000493:pharmacokinetics / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice
D002245:Carbon Dioxide; D002725:Chloroform; D005978:Glutathione