Witz G, Latriano L, Goldstein B D
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Department of Environmental and Community Medicine 08854-5635.
Environ Health Perspect. 1989 Jul;82:19-22. doi: 10.1289/ehp.898219.
We have previously hypothesized that ring-opened metabolites may play an important role in benzene toxicity. In this paper we review recent work related to this hypothesis. trans,trans-Muconaldehyde (TTM), a six-carbon diene dialdehyde, was shown by our laboratory to be a microsomal metabolite of benzene. This compound is a ring-opened metabolite of benzene that is hematotoxic in mice. The toxicity of TTM may stem in part from its ability to act as a direct-acting alkylating agent involving interaction with cellular sulfhydryls and/or amino groups. On the other hand, metabolism to the diacid trans,trans-muconic acid (MA), a known urinary metabolite of benzene, may represent detoxification since this results in loss of electrophilicity of the compound. Preliminary results indicate that TTM can be metabolized to MA in vitro and in vivo. The interaction of TTM in vitro with macrophages and neutrophils, key cells in the bone marrow, results in cell membrane changes, including loss of activity in the plasma membrane-bound NADPH-dependent oxidase and decreases in membrane lipid fluidity. Deoxyguanosine also was found to react with TTM, forming several different products. These findings may be due to TTM acting directly as an alkylating agent.
我们之前曾假设开环代谢产物可能在苯的毒性中起重要作用。在本文中，我们回顾了与该假设相关的近期研究工作。反，反-粘糠醛（TTM），一种六碳二烯二醛，被我们实验室证明是苯的微粒体代谢产物。该化合物是苯的一种开环代谢产物，对小鼠具有血液毒性。TTM的毒性可能部分源于其作为直接作用的烷基化剂与细胞巯基和/或氨基相互作用的能力。另一方面，代谢为二酸反，反-粘康酸（MA），一种已知的苯的尿液代谢产物，可能代表解毒过程，因为这会导致该化合物亲电性的丧失。初步结果表明，TTM在体外和体内均可代谢为MA。TTM在体外与骨髓中的关键细胞巨噬细胞和中性粒细胞相互作用，会导致细胞膜发生变化，包括质膜结合的NADPH依赖性氧化酶活性丧失以及膜脂流动性降低。还发现脱氧鸟苷与TTM反应，形成几种不同的产物。这些发现可能是由于TTM直接作为烷基化剂起作用。
