In vitro metabolism and bioactivation of 1,2,3-trichloropropane.
In vitro studies using rat and human hepatic microsomes have shown that the halogenated hydrocarbon 1,2,3-trichloropropane (TCP) is bioactivated to the direct acting mutagen 1,3-dichloroacetone (DCA). The presence of DCA in microsomal incubations was confirmed by gas chromatography-mass spectrometry. DCA formation was totally dependent on the presence of NADPH. The rate of DCA formation using rat and human microsomes was 0.268 +/- 0.029 and 0.026 +/- 0.006 nmol/min/mg protein +/- SE, respectively. When hepatic microsomes were isolated from rats pretreated with the cytochrome P-450 inducers, phenobarbital, and dexamethasone, 24- and 2.5-fold increases, respectively, in the rate of DCA production, were observed. Pretreatment with beta-naphthoflavone resulted in a 50% inhibition in DCA formation. The inhibitors of cytochromes P-450, SKF 525-A and 1-aminobenzotriazol, produced 85 and 70% inhibitions of DCA formation, respectively. When alcohol dehydrogenase and NADH were added to microsomal incubations, two TCP-related alcohols, 1,3-dichloro-2-propanol and 2,3-dichloropropanol, were formed. These alcohols are products of the initial microsomal metabolites, DCA and 2,3-dichloropropanal. [14C]TCP equivalents bound covalently to rat hepatic microsomal protein. This binding was increased 8-fold when hepatic microsomes from phenobarbital pretreated rats were used. The addition of either glutathione or N-acetylcysteine to the incubations completely inhibited this binding. In the presence of N-acetylcysteine, 1,3-(2-propanone)-bis-S-(N-acetylcysteine) (PDM) was the only N-acetylcysteine conjugate detected. It represented 87% of TCP microsomal metabolism. The formation of PDM implicates DCA as the major microsomal protein-binding metabolite of TCP. The formation of DCA, a direct-acting mutagen, may be responsible for the mutagenicity of TCP in systems using rat hepatic microsomes. Its role in the tumorigenicity and carcinogenicity of TCP remains to be established.
Weber
G L
GL
Department of Pharmacology/Toxicology, College of Pharmacy, University of Arizona, Tucson 85721.
Sipes
I G
IG
D000096:Acetone / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000494:pharmacology; D010634:Phenobarbital; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000096:Acetone; C009536:1,2,3-trichloropropane; D009249:NADP; C067434:1,3-dichloropropane; D011407:Propane; C047675:1,3-dichloroacetone; D010634:Phenobarbital