Kemper R A, Elfarra A A, Myers S R
Department of Comparative Biosciences, University of Wisconsin, 53706, USA.
Drug Metab Dispos. 1998 Sep;26(9):914-20.
3-Butene-1,2-diol (BDD), a metabolite of 1,3-butadiene, is rapidly metabolized by B6C3F1 mice at doses ranging from 10 to 250 mg/kg. Calculation of plasma clearance suggested that the kinetics of BDD metabolism were dose-dependent. Clearance varied 5-fold in this dose range. Urinary excretion of BDD was also dose-dependent but did not exceed 5% of the administered dose. A small fraction of the dose (<1%) was excreted as glucuronide or sulfate conjugates. Benzylimidazole, a cytochrome P450 inhibitor, decreased the clearance of BDD (25 mg/kg) by 44%, whereas 4-methylpyrazole, an alcohol dehydrogenase and cytochrome P450 inhibitor, decreased BDD clearance by 82%. BDD administration (250 mg/kg) resulted in depletion of hepatic and renal nonprotein thiols, by 48 and 22%, respectively. Pretreatment of mice with 4-methylpyrazole provided partial protection against depletion of nonprotein thiols, whereas pretreatment with benzylimidazole was ineffective. Incubation of BDD with NADPH and mouse liver microsomes resulted in time-dependent inactivation of p-nitrophenol hydroxylase (PNPH) activity, a marker for cytochrome P450. Inclusion of glutathione, with or without glutathione peroxidase, did not attenuate the inactivation of PNPH, whereas deferoxamine, superoxide dismutase, catalase, and mannitol provided modest protection. These results are consistent with suicide inhibition of PNPH by BDD, with a minor role for reactive oxygen species in the loss of PNPH. Treatment of mice with BDD (250 mg/kg) inactivated hepatic microsomal PNPH activity by 50% after 60 min. These results suggest that BDD is extensively and rapidly metabolized in mice, and they provide evidence for the formation of reactive intermediates that could play a role in the toxicity of 1, 3-butadiene.
3-丁烯-1,2-二醇（BDD）是1,3-丁二烯的一种代谢产物，在10至250毫克/千克的剂量范围内，B6C3F1小鼠能迅速将其代谢。血浆清除率的计算表明，BDD代谢动力学呈剂量依赖性。在此剂量范围内，清除率变化了5倍。BDD的尿排泄也呈剂量依赖性，但不超过给药剂量的5%。一小部分剂量（<1%）以葡萄糖醛酸或硫酸盐结合物的形式排泄。细胞色素P450抑制剂苄基咪唑使BDD（25毫克/千克）的清除率降低了44%，而醇脱氢酶和细胞色素P450抑制剂4-甲基吡唑使BDD清除率降低了82%。给予BDD（250毫克/千克）导致肝脏和肾脏非蛋白硫醇分别耗竭48%和22%。用4-甲基吡唑预处理小鼠可部分保护非蛋白硫醇不被耗竭，而用苄基咪唑预处理则无效。将BDD与NADPH和小鼠肝脏微粒体一起孵育导致对硝基苯酚羟化酶（PNPH）活性呈时间依赖性失活，PNPH是细胞色素P450的标志物。无论有无谷胱甘肽过氧化物酶，加入谷胱甘肽均不能减弱PNPH的失活，而去铁胺、超氧化物歧化酶、过氧化氢酶和甘露醇则提供了适度的保护。这些结果与BDD对PNPH的自杀性抑制一致，活性氧在PNPH丧失中起次要作用。用BDD（250毫克/千克）处理小鼠60分钟后，肝脏微粒体PNPH活性失活50%。这些结果表明，BDD在小鼠体内被广泛且迅速地代谢，并且它们为可能在1,3-丁二烯毒性中起作用的反应性中间体的形成提供了证据。
