Park S B, Osterloh J D, Vamvakas S, Hashmi M, Anders M W, Cashman J R
Department of Pharmaceutical Chemistry, University of California, San Francisco.
Chem Res Toxicol. 1992 Mar-Apr;5(2):193-201. doi: 10.1021/tx00026a008.
The metabolism of cysteine S-conjugates of both cis- and trans-1,3-dichloropropene in the presence of rat kidney microsomes and purified flavin-containing monooxygenase from hog liver was investigated in vitro. Preliminary studies with isolated rat kidney cells demonstrated that cysteine S-conjugates were quite toxic to the cells in a process which was consistent with a role of the flavin-containing monooxygenase in the bioactivation of the nephrotoxins. Putative S-oxide metabolites of cysteine S-conjugates were chemically synthesized, and diastereomers were separated and identified by spectroscopic means. The metabolic products of cysteine S-conjugates were identified by comparing the chemical properties of the metabolites with authentic synthetic cysteine S-conjugate S-oxides. Surprisingly, S-conjugate S-oxygenase activity was not observed with rat kidney microsomes but was present when cysteine S-conjugates were incubated with the highly purified flavin-containing monooxygenase from hog liver. The kinetic parameters indicated that considerable S-oxygenase stereoselectivity and structural selectivity was observed: cis cysteine S-conjugates were preferred substrates and N-acetylation of cysteine S-conjugates decreased substrate activity. S-Oxygenation was considerably diastereoselective and diastereoselectivity was much greater for cysteine S-conjugates with higher Vmax values. Cysteine S-conjugate S-oxides were not indefinitely stable, and under certain conditions, the S-oxides underwent a [2,3]-sigmatropic rearrangement to acrolein. Formation of acrolein or other electrophilic products from S-(chloropropenyl)cysteine conjugate S-oxides may contribute to the renal effects observed for S-(chloropropenyl)cysteine conjugates.(ABSTRACT TRUNCATED AT 250 WORDS)
在体外研究了顺式和反式1,3 - 二氯丙烯的半胱氨酸S - 共轭物在大鼠肾微粒体和猪肝纯化的含黄素单加氧酶存在下的代谢情况。对分离的大鼠肾细胞进行的初步研究表明，半胱氨酸S - 共轭物对细胞具有相当大的毒性，这一过程与含黄素单加氧酶在肾毒素生物活化中的作用一致。通过化学合成了半胱氨酸S - 共轭物的推定S - 氧化物代谢物，并通过光谱手段分离和鉴定了非对映异构体。通过将代谢物的化学性质与真实的合成半胱氨酸S - 共轭物S - 氧化物进行比较，鉴定了半胱氨酸S - 共轭物的代谢产物。令人惊讶的是，在大鼠肾微粒体中未观察到S - 共轭物S - 加氧酶活性，但当半胱氨酸S - 共轭物与猪肝高度纯化的含黄素单加氧酶一起孵育时则存在该活性。动力学参数表明观察到了相当大的S - 加氧酶立体选择性和结构选择性：顺式半胱氨酸S - 共轭物是优选的底物，半胱氨酸S - 共轭物的N - 乙酰化降低了底物活性。S - 氧化具有相当大的非对映选择性，对于具有较高Vmax值的半胱氨酸S - 共轭物，非对映选择性更大。半胱氨酸S - 共轭物S - 氧化物并非无限稳定，在某些条件下，S - 氧化物会发生[2,3] - 西格玛重排生成丙烯醛。由S - （氯丙烯基）半胱氨酸共轭物S - 氧化物形成丙烯醛或其他亲电产物可能导致观察到的S - （氯丙烯基）半胱氨酸共轭物的肾脏效应。（摘要截短于250字）
