Preston B D, Miller J A, Miller E C
Chem Biol Interact. 1984 Aug;50(3):289-312. doi: 10.1016/0009-2797(84)90038-3.
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.
2,2',5,5'-四氯联苯（TCB）的3,4-氧化物在37℃下于乙醇/中性缓冲液中与蛋氨酸或N-乙酰蛋氨酸的非酶促反应进行得非常缓慢，生成3-和4-甲硫基-TCB，二者比例约为1:1。在相似条件下，TCB 3,4-氧化物与半胱氨酸的反应速度快约100倍，生成3-和4-（半胱氨酸-S-基）-TCB，二者比例约为1:1，为主要产物。半胱氨酸-S-基-3,4-二氢-羟基-TCB(s)也是TCB 3,4-氧化物在二甲基亚砜/中性缓冲液中与半胱氨酸反应生成的次要产物。在37℃或70℃下，TCB 3,4-氧化物在乙醇/中性缓冲液中与谷胱甘肽未发生可检测到的反应，但在37℃下于乙醇/pH 8.7缓冲液中的反应进行得非常迅速，生成3-和4-（谷胱甘肽-S-基）-TCB及两种谷胱甘肽-S-基-TCB前体，比例约为1:1。在中性pH条件下，大鼠肝细胞溶胶催化TCB 3,4-氧化物与谷胱甘肽的反应中，谷胱甘肽-S-基-TCB(s)及其前体也能快速生成。谷胱甘肽-S-基-TCBs在温和条件下于含水乙醇溶液中浓缩时容易降解，生成初步鉴定为[N-(5-羧基-1-吡咯啉-2-基)-1-甘氨酰半胱氨酸-S-基]-TCBs、(1-甘氨酰半胱氨酸-S-基)-TCBs和2-氧代吡咯烷-5-羧酸的化合物。单次给予TCB的大鼠在最初4天内，粪便中排出约0.07%的剂量，分别为3-甲硫基-TCB、4-甲硫基-TCB、4-甲基磺酰基-TCB、甲硫基羟基-TCBs（初步鉴定）和巯基-TCB(s)（初步鉴定），比例约为1:5:0.1:0.1:0.05。给予等摩尔剂量TCB 3,4-氧化物的大鼠排出这些粪便代谢物的比例相似，但量约大10倍。单次给予TCB的小鼠在最初4天内，粪便中排出约0.1%的剂量，分别为3-甲硫基-TCB、4-甲硫基-TCB和3-甲基磺酰基-TCB，比例约为1.5:1:0.05。在单次给予TCB的插管大鼠胆汁中未检测到甲硫基-TCBs（低于剂量的0.0004%）。约1.5%的TCB剂量以谷胱甘肽-S-基-TCB(s)及其前体的形式经胆汁排出。总体而言，数据表明TCB 3,4-氧化物是TCB甲硫基代谢物形成过程中的主要代谢中间体。
