Hashmi M, Vamvakas S, Anders M W
Department of Pharmacology, University of Rochester, New York 14642.
Chem Res Toxicol. 1992 May-Jun;5(3):360-5. doi: 10.1021/tx00027a007.
S-(3-Oxopropyl)glutathione, the glutathione conjugate of acrolein, has been reported to be nephrotoxic. The objective of the present studies was to investigate the bioactivation mechanism of the analogues S-(3-oxopropyl)-N-acetyl-L-cysteine (1) and S-(3-oxopropyl)-N-acetyl-L-cysteine S-oxide (2) and to test the hypothesis that the cytotoxicity of 1 is associated with its latent potential to release acrolein in kidney cells. Mechanistic considerations indicated that sulfoxidation of sulfide 1 to form S-oxide 2 and a subsequent general-base-catalyzed beta-elimination reaction would release the cytotoxin acrolein. Hence the release of acrolein from 1 and 2 was studied in chemical systems, and their cytotoxicity was investigated in cultured LLC-PK1 cells and in isolated rat renal proximal tubular cells. Acrolein formation from S-oxide 2, but not from sulfide 1, was observed under basic conditions and with phosphate as the base. Kinetic analysis indicated that a general-base-catalyzed reaction was involved. Both S-conjugates 1 and 2 were cytotoxic in LLC-PK1 cells and in isolated rat renal proximal tubular cells, and the cytotoxicity of sulfide 1, but not of S-oxide 2, in isolated renal proximal tubular cells was reduced in presence of methimazole, an inhibitor of the flavin-containing monooxygenase. These findings indicate that the cytotoxicity of S-conjugate 1 is associated with a novel bioactivation mechanism that involves sulfoxidation followed by a general-base-catalyzed elimination of acrolein from S-oxide 2.
已报道丙烯醛的谷胱甘肽共轭物S-(3-氧代丙基)谷胱甘肽具有肾毒性。本研究的目的是探究类似物S-(3-氧代丙基)-N-乙酰-L-半胱氨酸(1)和S-(3-氧代丙基)-N-乙酰-L-半胱氨酸S-氧化物(2)的生物活化机制，并验证1的细胞毒性与其在肾细胞中释放丙烯醛的潜在可能性相关这一假说。从机理上考虑，硫化物1氧化形成S-氧化物2，随后发生一般碱催化的β-消除反应会释放出细胞毒素丙烯醛。因此，在化学体系中研究了1和2中丙烯醛的释放情况，并在培养的LLC-PK1细胞和分离的大鼠肾近端小管细胞中研究了它们的细胞毒性。在碱性条件下且以磷酸盐作为碱时，观察到从S-氧化物2而非硫化物1形成丙烯醛。动力学分析表明涉及一般碱催化反应。S-共轭物1和2在LLC-PK1细胞和分离的大鼠肾近端小管细胞中均具有细胞毒性，在含黄素单加氧酶的抑制剂甲巯咪唑存在的情况下，分离的肾近端小管细胞中硫化物1而非S-氧化物2的细胞毒性降低。这些发现表明，S-共轭物1的细胞毒性与一种新的生物活化机制有关，该机制涉及硫化氧化，随后是一般碱催化从S-氧化物2中消除丙烯醛。
