Coles B, Srai S K, Waynforth H B, Ketterer B
Chem Biol Interact. 1983 Dec;47(3):307-23. doi: 10.1016/0009-2797(83)90166-7.
In the normal rat given a single dose of one mg N,N-dimethyl-4-aminoazobenzene (DAB) via the hepatic portal vein the following biliary metabolites reached their maximal rates of excretion in the sequence: 4'-sulphonyloxy-DAB, N-(glutathione-S-methylene)-4-aminoazobenzene (GSCH2AB), 4'-sulphonyloxy-N-methyl-4-aminoazobenzene (4'-sulphonyloxy-MAB) 4'-sulphonyloxy-GSCH2AB and MAB-4'-beta-glucuronide. The unusual and relatively unstable N-methylene glutathione conjugates were major metabolites accounting for up to 70% of the whole. It was shown that all the 4-aminoazobenzene (AB) and perhaps all of the 4'-sulphonyloxy-AB, which may be observed in bile, are artefacts due to decomposition of GSCH2AB and 4'-sulphonyloxy-GSCH2AB respectively and that biliary excretion of N-methyl oxidised products of MAB and 4'-hydroxy-MAB is dependent on their conversion to the GSH conjugates, GSCH2AB and 4'-hydroxy-GSCH2AB respectively. Sulphotransferase inhibition by pentachlorophenol caused a reduction in the excretion of all sulphate conjugates, but biliary excretion as a whole was not reduced significantly due to a compensatory increase in the excretion of MAB-4'-beta-glucuronide and the appearance of 4'-OH-GSCH2AB. Glutathione (GSH) depletion by diethylmaleate caused a reduction in biliary metabolites of DAB by lowering the levels of GSH conjugates. This was because the amount of N-methyl oxidation of MAB and 4'-hydroxy-MAB were proportional to the amount of GSH present. The fall in N-methyl oxidation was not compensated for by an increase in 4'-hydroxylation and was accompanied by a delay in the appearance of 4'-hydroxylated metabolites. The administration of potential precursors of 4'-sulphonyloxy-GSCH2AB establishes the sequence of reactions resulting in its formation to be 4'-hydroxylation, N-methyl oxidation, GSH conjugation and O-sulphation.
给正常大鼠经肝门静脉单次注射1毫克N，N - 二甲基 - 4 - 氨基偶氮苯（DAB）后，下列胆汁代谢产物按以下顺序达到其最大排泄速率：4'- 磺酰氧基 - DAB、N - （谷胱甘肽 - S - 亚甲基）- 4 - 氨基偶氮苯（GSCH2AB）、4'- 磺酰氧基 - N - 甲基 - 4 - 氨基偶氮苯（4'- 磺酰氧基 - MAB）、4'- 磺酰氧基 - GSCH2AB和MAB - 4'- β - 葡萄糖醛酸苷。异常且相对不稳定的N - 亚甲基谷胱甘肽共轭物是主要代谢产物，占总量的70%。结果表明，胆汁中可能观察到的所有4 - 氨基偶氮苯（AB）以及可能所有的4'- 磺酰氧基 - AB，分别是由于GSCH2AB和4'- 磺酰氧基 - GSCH2AB分解产生的假象，并且MAB和4'- 羟基 - MAB的N - 甲基氧化产物的胆汁排泄分别取决于它们转化为谷胱甘肽共轭物GSCH2AB和4'- 羟基 - GSCH2AB。五氯苯酚对磺基转移酶的抑制导致所有硫酸盐共轭物的排泄减少，但由于MAB - 4'- β - 葡萄糖醛酸苷排泄的代偿性增加和4'- OH - GSCH2AB的出现，胆汁排泄总体上没有显著减少。马来酸二乙酯导致的谷胱甘肽（GSH）耗竭通过降低GSH共轭物水平而使DAB的胆汁代谢产物减少。这是因为MAB和4'- 羟基 - MAB的N - 甲基氧化量与存在的GSH量成正比。N - 甲基氧化的下降没有通过4'- 羟基化的增加得到补偿，并且伴随着4'- 羟基化代谢产物出现的延迟。4'- 磺酰氧基 - GSCH2AB潜在前体的给药确定了导致其形成的反应顺序为4'- 羟基化、N - 甲基氧化、GSH共轭和O - 硫酸化。
