Schrenk D
Food Chemistry and Environmental Toxicology, University of Kaiserslautern, Germany.
Biochem Pharmacol. 1998 Apr 15;55(8):1155-62. doi: 10.1016/s0006-2952(97)00591-1.
The induction of a number of drug-metabolizing enzymes is among the best-understood biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related agonists of the aryl hydrocarbon receptor (AhR). Among the cytochrome P450s (CYPs), the genes encoding CYP1A1, 1A2, and 1B1 are responsive to AhR agonists, i.e. their expression is inducible in various mammalian tissues and organs as well as in many types of cell lines and primary cells in culture. In addition, an aldehyde dehydrogenase, an NADPH-quinone-oxidoreductase, and the phase II conjugating enzymes glutathione-S-transferase (GST) Ya and UDP-glucuronosyltransferase 1A1 have been identified as responsive to AhR agonists. Induced expression of these members of the AhR gene battery is thought to be aimed at an improved elimination of the inducing agent and its metabolites. However, the identity of the physiological ligand(s) of the AhR is still obscure. The consequences of induced expression of AhR-regulated genes encoding drug-metabolizing enzymes have been investigated in human populations, e.g. in smokers, and in various experimental models. A prominent example of increased adverse effects due to the induction of CYP1A isozymes is the metabolic activation of carcinogenic aromatic amines and polycyclic aromatic hydrocarbons. An increasing amount of data is also available on the impact of dioxin-type induction on the metabolism of drugs, food constituents, and endogenous substrates. For example, the hepatic clearance of the drug theophylline, which is widely used in asthma therapy, is enhanced significantly in smokers. Increased glucuronidation of thyroxine in rats treated with TCDD or other potent AhR agonists is thought to result in hypothyroxinemia and its biological consequences, such as sustained hyperplasia of the thyroid, bearing a higher risk of thyroid cancer. The relevance of these observations for humans exposed to dioxin-type inducers is discussed.
诱导多种药物代谢酶是2,3,7,8-四氯二苯并-对-二噁英（TCDD）及芳烃受体（AhR）相关激动剂最为人熟知的生化效应之一。在细胞色素P450（CYP）中，编码CYP1A1、1A2和1B1的基因对AhR激动剂有反应，即它们的表达在各种哺乳动物组织和器官以及许多类型的细胞系和原代培养细胞中均可诱导。此外，一种醛脱氢酶、一种NADPH-醌氧化还原酶以及II相结合酶谷胱甘肽-S-转移酶（GST）Ya和尿苷二磷酸葡萄糖醛酸基转移酶1A1已被确定对AhR激动剂有反应。AhR基因群中这些成员的诱导表达被认为旨在更好地清除诱导剂及其代谢产物。然而，AhR的生理配体的身份仍然不明。在人群中，如吸烟者，以及在各种实验模型中，已经研究了编码药物代谢酶的AhR调控基因诱导表达的后果。由于CYP1A同工酶诱导导致不良反应增加的一个突出例子是致癌芳香胺和多环芳烃的代谢活化。关于二噁英类诱导对药物、食物成分和内源性底物代谢的影响，也有越来越多的数据。例如，广泛用于哮喘治疗的药物茶碱在吸烟者中的肝脏清除率显著提高。在用TCDD或其他强效AhR激动剂处理过的大鼠中，甲状腺素葡萄糖醛酸化增加被认为会导致甲状腺素血症及其生物学后果，如甲状腺持续增生，从而增加患甲状腺癌的风险。本文讨论了这些观察结果与接触二噁英类诱导剂的人类的相关性。
