Mutagen activation of 1,2-dibromo-3-chloropropane by cytosolic glutathione S-transferases and microsomal enzymes.
It is not clear whether glutathione (GSH) conjugation to 1,2-dibromo-3-chloropropane (DBCP) results in genotoxic activation. Therefore S9, cytosolic, and microsomal fractions from uninduced rat liver were evaluated for their relative ability to activate DBCP in a modified Ames system. The S9 enzymes, either alone or in combination with exogenous GSH, did not enhance the mutagenicity of DBCP; identical results were obtained with cytosolic enzymes. Significant mutagenic activation of DBCP was produced by either S9 or microsomal fractions in the presence of NADPH. Activation was proportional to cytochrome P-450 concentrations, and was diminished by exogenous GSH. The protection against genotoxicity exerted by GSH did not require cytosolic glutathione S-transferases (GST). Thus, mutagenic activation of DBCP as obtained with S9 fractions is primarily due to biotransformation by microsomal rather than by cytosolic enzymes. Kinetic studies of cytosol-catalyzed conjugation of GSH to DBCP revealed tissue-specific differences in apparent Km and Vmax. Renal and testicular GSTs were associated with 28-46% smaller Vmax values when compared to hepatic GSTs (31.2 +/- 1.9 nmol/min X mg protein). However, renal and testicular GSTs had relatively higher affinities for DBCP. Thus, extrahepatic tissues possess significant capacity to conjugate GSH to DBCP. DBCP-GSH conjugates may undergo enzymatic modification by extrahepatic peptidase and beta-lyase to yield other sulfur-containing moieties that perhaps mediate DBCP's extrahepatic toxicity.
D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013737:Testis / Q000378:metabolism
D009153:Mutagens; C007318:1,2-dibromo-3-chloropropane; D005982:Glutathione Transferase; D005978:Glutathione; D011407:Propane