Carlson Gary P
School of Health Sciences, Purdue University, West Lafayette, IN 47907-1338, USA.
Toxicology. 2002 Sep 30;179(1-2):129-36. doi: 10.1016/s0300-483x(02)00340-2.
Styrene is known to be both hepatotoxic and pneumotoxic in rodents. 4-Vinylphenol (4-VP) has been shown to be a minor metabolite of styrene in some studies and is a more potent toxicant in mice than either styrene or styrene oxide. 4-VP is metabolized primarily by CYP2E1 and CYP2F2 to an unknown metabolite. The purpose of this study was to use inhibitors of these cytochromes P450 to address the question of whether the parent compound or a metabolite is responsible for 4-VP induced toxicity. Rats as well as mice were found to be susceptible to the toxicity of 4-VP. Prior treatment with either diethyldithiocarbamate or 5-phenyl-1-pentyne as inhibitors of CYP2E1 and CYP2F2 prevented or greatly decreased the hepatotoxicity of 4-VP as assessed by measuring serum sorbitol dehydrogenase and its pneumotoxicity as determined by measurements of cells, protein and lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluid. Thus the hepatotoxicity and pneumotoxicity of 4-VP are due to a metabolite(s) and not the parent compound.
已知苯乙烯对啮齿动物具有肝毒性和肺毒性。在一些研究中，4-乙烯基苯酚（4-VP）已被证明是苯乙烯的一种次要代谢产物，并且在小鼠中它比苯乙烯或环氧苯乙烯更具毒性。4-VP主要通过CYP2E1和CYP2F2代谢为一种未知代谢产物。本研究的目的是使用这些细胞色素P450的抑制剂来解决母体化合物还是代谢产物导致4-VP诱导毒性这一问题。发现大鼠和小鼠均对4-VP的毒性敏感。用二乙基二硫代氨基甲酸盐或5-苯基-1-戊炔作为CYP2E1和CYP2F2的抑制剂进行预处理，通过测量血清山梨醇脱氢酶评估，可预防或大大降低4-VP的肝毒性；通过测量支气管肺泡灌洗液中的细胞、蛋白质和乳酸脱氢酶（LDH）活性来确定，可降低其肺毒性。因此，4-VP的肝毒性和肺毒性是由一种或多种代谢产物引起的，而非母体化合物。
