Badger T M, Ronis M J, Ingelman-Sundberg M, Hakkak R
Department of Pediatrics, Arkansas Children's Hospital Research Institute, Little Rock, USA.
Eur J Biochem. 1995 Jun 15;230(3):914-9. doi: 10.1111/j.1432-1033.1995.tb20636.x.
Continuous, long-term intragastric infusions of ethanol leads to a two-step induction of hepatic cytochrome P450 2E1 (CYP2E1) that is correlated with blood ethanol concentrations (BECs) and urine alcohol concentrations (UECs). In addition, long-term and continuous ethanol infusion does not produce a steady-state BEC, but results in pulsatile BECs and UECs having peak-peak duration of approximately 6 days and ethanol concentrations ranging from near zero to over 500 mg/dl. In the present study, rats were treated with ethanol (levels reaching 13 g.kg-1.day-1) for 38 days in the presence of compounds reported to block CYP2E1 activity or expression, to study the possible involvement of CYP2E1 in the pulsatile BECs. The inhibitors used were chlormethiazole (CMZ); diallysulfide (DAS); phenethyl isothiocyanate (PET) and dihydrocapsacin (DHC). Hepatic microsomal metabolism of carbon tetrachloride and p-nitrophenol, as well as mean CYP2E1 apoprotein levels, were significantly greater (P < or = 0.05) in ethanol-treated rats than in control rats, whereas rats treated with DAS, CMZ or PET had significantly (P < or = 0.05) reduced p-nitrophenol and carbon tetrachloride metabolism and lower CYP2E1 apoprotein levels compared to those of ethanol controls. UECs were variable in all ethanol-treated groups and there was a typical pulsatile pattern that had a mean interpulse interval (the number of days between the peaks of two consecutive pulses) ranging over 5.4 +/- 0.3-6.0 +/- 0.7 days and a mean amplitude (nadir to peak UEC) of 415 +/- 39-337 +/- 33 mg/dl. None of the putative CYP2E1 blockers altered the pulsatile nature of ethanol in urine. Our results suggest that pulsatile UECs are not the result of variations in the amount of CYP2E1.
持续、长期胃内输注乙醇会导致肝脏细胞色素P450 2E1（CYP2E1）分两步诱导，这与血液乙醇浓度（BECs）和尿乙醇浓度（UECs）相关。此外，长期持续输注乙醇不会产生稳态BEC，而是导致脉动性BECs和UECs，其峰-峰持续时间约为6天，乙醇浓度范围从接近零到超过500mg/dl。在本研究中，在存在据报道可阻断CYP2E1活性或表达的化合物的情况下，用乙醇（水平达到13g·kg-1·天-1）处理大鼠38天，以研究CYP2E1在脉动性BECs中可能的作用。使用的抑制剂为氯美噻唑（CMZ）；二烯丙基硫醚（DAS）；苯乙基异硫氰酸酯（PET）和二氢辣椒素（DHC）。与对照大鼠相比，乙醇处理的大鼠中四氯化碳和对硝基苯酚的肝微粒体代谢以及CYP2E1载脂蛋白平均水平显著更高（P≤0.05），而与乙醇对照组相比，用DAS、CMZ或PET处理的大鼠对硝基苯酚和四氯化碳代谢显著降低（P≤0.05），CYP2E1载脂蛋白水平更低。所有乙醇处理组的UECs都有变化，并且有典型的脉动模式，平均脉冲间隔（两个连续脉冲峰值之间的天数）范围为5.4±0.3 - 6.0±0.7天，平均幅度（UEC最低点到峰值）为415±39 - 337±33mg/dl。没有一种假定的CYP2E1阻滞剂改变尿液中乙醇的脉动性质。我们的结果表明，脉动性UECs不是CYP2E1量变化的结果。
