Covalent interactions of 1,2,3-trichloropropane with hepatic macromolecules: studies in the male F-344 rat.
Preliminary investigations into the role of biotransformation in 1,2,3-trichloropropane (TCP)-induced tumor formation have been undertaken. Male F-344 rats were administered 30 mg/kg [14C]TCP (100 microCi/kg) ip and killed 4 hr later. The extent of covalent binding to hepatic protein, DNA, and RNA was 418, 244, and 432 pmol [14C]TCP equivalents/mg, respectively. An in vivo covalent binding time course showed no significant change in [14C]TCP equivalents bound to hepatic DNA (1-48 hr), while binding to protein was maximal by 4 hr and decreased significantly by 48 hr. The binding of TCP-associated radioactivity to hepatic protein and DNA was shown to be cumulative for two and three doses when given 24 hr apart. Pretreatment of animals with phenobarbital caused a decrease while pretreatment with SKF 525-A caused an increase in covalent binding of [14C]TCP equivalents to protein and DNA. Pretreatment of rats with beta-naphthoflavone did not alter the covalent binding of [14C]TCP equivalents to protein or DNA. However, glutathione depletion with L-buthionine-(R,S)-sulfoximine increased binding to protein by 342% while it decreased binding to DNA by 56%. Intraperitoneal administration of TCP also depleted hepatic GSH by 41 and 61% 2 hr after doses of 30 and 100 mg/kg. The in vivo binding data suggest a dual role for GSH in the bioactivation of TCP. It may, in part, be that GSH is involved in the bioactivation and covalent binding of TCP to hepatic DNA. However, it also appears to detoxify a reactive intermediate(s) that binds to protein.
Weber
G L
GL
Department of Pharmacology/Toxicology, College of Pharmacy, University of Arizona, Tucson 85721.
Sipes
I G
IG
D000704:Analysis of Variance; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001571:Benzoflavones / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D019324:beta-Naphthoflavone
D000963:Antimetabolites; D001571:Benzoflavones; D011506:Proteins; D011725:Pyridines; C013109:metapyrone; D008717:Methionine Sulfoximine; C009536:1,2,3-trichloropropane; D019328:Buthionine Sulfoximine; D019324:beta-Naphthoflavone; D012313:RNA; D004247:DNA; D011407:Propane; D010634:Phenobarbital