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.