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

Bradley D. Preston, James A. Miller, Elizabeth C. Miller

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

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°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°C or 70°C, but reaction in ethanol/pH 8.7 buffer at 37°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 (<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.

Original languageEnglish (US)
Pages (from-to)289-312
Number of pages24
JournalChemico-Biological Interactions
Volume50
Issue number3
DOIs
StatePublished - Aug 1984
Externally publishedYes

Keywords

  • 22′55′-Tetrachlorobiphenyl 3
  • 4-oxide
  • Cysteine
  • Glutathione
  • Methionine
  • Methylthio
  • Polychlorinated biphenyls

ASJC Scopus subject areas

  • Toxicology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this