Custodio J B, Palmeira C M, Moreno A J, Wallace K B
Department of Biochemistry and Molecular Biology, University of Minnesota School of Medicine, Duluth 55812, USA.
Toxicol Sci. 1998 May;43(1):19-27. doi: 10.1006/toxs.1998.2448.
Acrylic acid (AA) is used widely in the synthesis of esters essential in the production of paints, adhesives, plastics, and coatings. The minimal systemic toxicity of AA is attributed to its rapid oxidation to acetyl-CoA and CO2 via the vitamin B12-independent beta-oxidation pathway. This oxidation is localized to the mitochondria and preliminary evidence suggests a possible inhibition of mitochondrial metabolism by acrylic acid. The purpose of this investigation was to evaluate whether AA interferes with mitochondrial bioenergetics in vitro. Incubation of isolated rat liver mitochondrial with AA resulted in a dose-dependent induction of the mitochondrial permeability transition (MPT). This was evidenced by an increased sensitivity to calcium-induced stimulation of state 4 oxygen consumption, depolarization of membrane potential, and swelling, all of which were prevented by preincubating the mitochondrial with cyclosporine A, a potent and specific inhibitor of the mitochondrial permeability transition pore. Both N-ethylmaleimide (NEM) and dithiothreitol (DTT) showed only partial protection against induction of the MPT by AA. Associated with the induction of the MPT by AA was the loss of mitochondrial glutathione (GSH), which was due to efflux from the matrix rather than oxidation to GSSG. Cyclosporine A, by inhibiting the permeability transition, prevented the AA-induced loss of mitochondrial GSH. In conclusion, AA increases the sensitivity of isolated mitochondria in vitro to the calcium-dependent induction of the MPT. Although the molecular mechanism has yet to be defined, it does not appear to be related to the oxidation of critical thiols.
丙烯酸（AA）广泛用于合成涂料、粘合剂、塑料和涂层生产中必不可少的酯类。AA的全身毒性极小，这归因于它通过不依赖维生素B12的β-氧化途径迅速氧化为乙酰辅酶A和二氧化碳。这种氧化定位于线粒体，初步证据表明丙烯酸可能抑制线粒体代谢。本研究的目的是评估AA在体外是否会干扰线粒体生物能量学。将分离的大鼠肝线粒体与AA一起孵育会导致线粒体通透性转换（MPT）呈剂量依赖性诱导。这表现为对钙诱导的状态4氧消耗刺激的敏感性增加、膜电位去极化和肿胀，预先用环孢素A（一种强效且特异性的线粒体通透性转换孔抑制剂）孵育线粒体可防止所有这些情况发生。N-乙基马来酰亚胺（NEM）和二硫苏糖醇（DTT）对AA诱导的MPT仅显示出部分保护作用。与AA诱导MPT相关的是线粒体谷胱甘肽（GSH）的丧失，这是由于从基质中流出而非氧化为氧化型谷胱甘肽（GSSG）所致。环孢素A通过抑制通透性转换，防止了AA诱导的线粒体GSH丧失。总之，AA在体外增加了分离线粒体对钙依赖性MPT诱导的敏感性。尽管分子机制尚未明确，但似乎与关键巯基的氧化无关。
