Agyeman A A, Sultatos L G
Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark 07103, USA.
Toxicology. 1998 Jul 17;128(3):207-18. doi: 10.1016/s0300-483x(98)00082-1.
Parathion, like most organophosphorus insecticides currently in use, must undergo cytochrome P450(P450)-dependent activation in order to exert its acute mammalian toxicity (cholinergic crisis). Since P450 isoforms play such an important role in mediating the toxicity of parathion and related insecticides, factors which significantly alter P450 activities, such as exposure to certain xenobiotics, can also be expected to affect the toxicity of these potentially hazardous insecticides. Cimetidine is a H2-histamine antagonist that has been shown to inhibit several P450-isoforms. In addition, administration of cimetidine has been reported to result in clinically significant pharmacokinetic interactions with a wide variety of drugs. In the present study coexposure to cimetidine and parathion resulted in a moderate increase in the toxicity of this pesticide. However, coexposure to cimetidine and paraoxon did not alter the toxicity of the organophosphate, indicating that cimetidine likely affected P450-dependent formation of paraoxon from parathion. In vitro incubations of mouse hepatic microsomes demonstrated that, in addition to reducing the velocity of P450-dependent metabolism of parathion, cimetidine increased the proportion of paraoxon formed (activation). and decreased the proportion of p-nitrophenol formed (detoxification). Since parathion is not eliminated significantly by other routes in the mouse, the bulk of parathion in vivo was metabolized by P450 (although more slowly) in the presence of cimetidine, leading to a greater amount of paraoxon produced, and therefore greater toxicity. Incubations with individual P450 isoforms suggested that cimetidine could act by inhibition of P450 isoforms that detoxify parathion to a greater degree than cimetidine-resistant isoforms, and/or cimetidine could alter the proportions of detoxification versus activation of certain individual isoforms.
对硫磷与目前使用的大多数有机磷杀虫剂一样，必须经过细胞色素P450（P450）依赖性激活才能发挥其急性哺乳动物毒性（胆碱能危象）。由于P450同工型在介导对硫磷及相关杀虫剂的毒性方面发挥着如此重要的作用，因此，显著改变P450活性的因素，如接触某些外源性物质，也有望影响这些潜在危险杀虫剂的毒性。西咪替丁是一种H2组胺拮抗剂，已被证明可抑制多种P450同工型。此外，据报道，服用西咪替丁会导致与多种药物发生具有临床意义的药代动力学相互作用。在本研究中，同时接触西咪替丁和对硫磷会导致这种农药的毒性适度增加。然而，同时接触西咪替丁和对氧磷并没有改变有机磷的毒性，这表明西咪替丁可能影响了对硫磷经P450依赖性形成对氧磷的过程。小鼠肝微粒体的体外孵育表明，除了降低对硫磷经P450依赖性代谢的速度外，西咪替丁还增加了形成的对氧磷比例（激活），并降低了形成的对硝基苯酚比例（解毒）。由于对硫磷在小鼠体内不会通过其他途径被显著清除，因此在存在西咪替丁的情况下，体内大部分对硫磷会被P450代谢（尽管速度较慢），从而产生更多的对氧磷，进而导致更大的毒性。与单个P450同工型的孵育表明，西咪替丁可能通过抑制比对硫磷抗性同工型更能解毒对硫磷的P450同工型来发挥作用，和/或西咪替丁可能改变某些单个同工型解毒与激活的比例。
