Crouch J Y, Solomon L R
Veterans Administration Medical Center, West Haven, CT 06516.
Biochem Pharmacol. 1989 Oct 15;38(20):3431-7. doi: 10.1016/0006-2952(89)90111-1.
To better define the significance and mechanism of acetaldehyde-mediated transaminase inhibition, acetaldehyde metabolism was studied in rat liver homogenates and cytosols. When either preparation was incubated at 37 degrees with 1.5 mM acetaldehyde for 4 hr, acetaldehyde levels fell rapidly in the first 30 min and little inhibition of aspartate aminotransferase (GOT) or alanine aminotransferase (GPT) resulted. In contrast, incubation with 50 mM ethanol also resulted in a peak acetaldehyde level of 1.0 to 1.5 mM by 2 hr, but this level was then maintained for the next 2 hr and transaminases were inhibited by 20-35%. Sequential addition of low dose (125-250 microM) pulses of acetaldehyde to rat liver preparations resulted in a progressive decrease in the rate of acetaldehyde disappearance. When the pulsing schedule was adjusted accordingly to maintain acetaldehyde levels between 50 and 250 microM for 8 hr, transaminases were again inhibited by 20-40%. Finally, addition of 1-5 mM pyridoxal and pyridoxal 5'-phosphate, aldehydic B6 vitamers, to cytosols 2-4 hr after pulsing with acetaldehyde was begun, almost completely prevented further transaminase inhibition. In contrast, the non-aldehydic B6 vitamers, pyridoxine, pyridoxamine and pyridoxamine 5'-phosphate, did not affect acetaldehyde-mediated transaminase inhibition. These findings suggest that (1) prolonged exposure to low levels of acetaldehyde impairs acetaldehyde metabolism in rat liver homogenates and cytosols; (2) acetaldehyde toxicity may be more dependent on sustained exposure to acetaldehyde than on the peak level of acetaldehyde attained; and (3) aldehydic B6 vitamers can modify on-going acetaldehyde-mediated transaminase inhibition.
为了更好地确定乙醛介导的转氨酶抑制作用的意义和机制，我们在大鼠肝脏匀浆和胞质溶胶中研究了乙醛代谢。当任何一种制剂在37℃下与1.5 mM乙醛孵育4小时时，乙醛水平在前30分钟迅速下降，天冬氨酸转氨酶（GOT）或丙氨酸转氨酶（GPT）几乎没有受到抑制。相比之下，与50 mM乙醇孵育2小时后，乙醛水平也会达到1.0至1.5 mM的峰值，但该水平在接下来的2小时内保持不变，转氨酶被抑制20 - 35%。向大鼠肝脏制剂中依次添加低剂量（125 - 250 microM）的乙醛脉冲会导致乙醛消失速率逐渐降低。当相应调整脉冲时间表以将乙醛水平维持在50至250 microM之间8小时时，转氨酶再次被抑制20 - 40%。最后，在开始用乙醛脉冲处理2 - 4小时后，向胞质溶胶中添加1 - 5 mM的吡哆醛和磷酸吡哆醛（醛基B6维生素），几乎完全阻止了进一步的转氨酶抑制。相比之下，非醛基B6维生素、吡哆醇、吡哆胺和磷酸吡哆胺对乙醛介导的转氨酶抑制没有影响。这些发现表明：（1）长时间暴露于低水平的乙醛会损害大鼠肝脏匀浆和胞质溶胶中的乙醛代谢；（2）乙醛毒性可能更多地取决于持续暴露于乙醛，而不是所达到的乙醛峰值水平；（3）醛基B6维生素可以改变正在进行的乙醛介导的转氨酶抑制作用。
