Reactions of 2,2',5,5'-tetrachlorobiphenyl 3,4-oxide with methionine, cysteine and glutathione in relation to the formation of methylthio-metabolites of 2,2',5,5'-tetrachlorobiphenyl in the rat and mouse.
Non-enzymatic reactions of the 3,4-oxide of 2,2'5,5'-tetrachlorobiphenyl (TCB) with methionine or N-acetylmethionine in ethanol/neutral buffer at 37 degrees C proceeded very slowly to yield an approx. 1:1 ratio of 3- and 4-methylthio-TCB. Under similar conditions reaction of TCB 3,4-oxide with cysteine proceeded about 100 times more rapidly to yield an approx. 1:1 ratio of 3- and 4-(cystein-S-yl)-TCB as the major products. Cystein-S-yl-3,4-dihydro-hydroxy-TCB(s) was also formed as a minor product from reaction of TCB 3,4-oxide with cysteine in dimethyl sulfoxide/neutral buffer. TCB 3,4-oxide did not react detectably with glutathione in ethanol/neutral buffer at 37 degrees C or 70 degrees C, but reaction in ethanol/pH 8.7 buffer at 37 degrees C proceeded very rapidly to yield about a 1:1 ratio of 3- and 4-(glutathion-S-yl)-TCB and of two glutathion-S-yl-TCB precursors. Glutathion-S-yl-TCB(s) and its precursor(s) were also formed rapidly in a rat liver cytosol-catalyzed reaction of TCB 3,4-oxide with glutathione at neutral pH. The glutathion-S-yl-TCBs readily degraded upon concentration in aqueous alcohol solutions under mild conditions to yield compounds tentatively identified as [N-(5-carboxy-1-pyrrolin-2-yl)-1-glycinocystein-S-yl]-TCBs, (1-glycinocystein-S-yl)-TCBs and 2-oxopyrrolidine-5-carboxylic acid. Rats given a single dose of TCB excreted about 0.07% of the dose in the feces during the first 4 days as 3-methylthio-TCB, 4-methylthio-TCB, 4-methylsulfonyl-TCB, methylthio-hydroxy-TCBs (tentatively identified) and mercapto-TCB(s) (tentatively identified) in about a 1:5:0.1:0.1:0.05 ratio, respectively. Rats given an equimolar dose of TCB 3,4-oxide excreted similar ratios of these fecal metabolites in approx. 10-fold greater quantities. Mice given TCB excreted about 0.1% of the dose in the feces during the first 4 days as 3-methylthio-TCB, 4-methylthio-TCB and 3-methylsulfonyl-TCB in about a 1.5:1:0.05 ratio, respectively. Methylthio-TCBs were not detected (less than 0.0004% of the dose) in the bile of a cannulated rat given a single dose of TCB. About 1.5% of the TCB dose was excreted in the bile as glutathion-S-yl-TCB(s) and its precursor(s). Collectively, the data indicate that TCB 3,4-oxide is a primary metabolic intermediate in the formation of methylthio-metabolites of TCB.
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D005243:Feces / Q000032:analysis; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011078:Polychlorinated Biphenyls / Q000378:metabolism*; D051381:Rats; D013055:Spectrophotometry, Infrared
C009407:2,5,2',5'-tetrachlorobiphenyl; C042328:2,2',5,5'-tetrachlorobiphenyl 3,4-oxide; C006379:N-acetylmethionine; D008715:Methionine; D011078:Polychlorinated Biphenyls; D005978:Glutathione; D003545:Cysteine