Reinke L A, Belinsky S A, Kauffman F C, Evans R K, Thurman R G
Biochem Pharmacol. 1982 Apr 15;31(8):1621-8. doi: 10.1016/0006-2952(82)90390-2.
Sorbitol and ethanol were shown to have opposite effects on p-nitroanisole O-demethylation in perfused livers from fasted, phenobarbital-treated rats. Sorbitol (2 mM) stimulated drug metabolism by 50% while ethanol (20 mM) caused 80% inhibition. Both sorbitol and ethanol infusion decreased the NAD+/NADH ratio and increased fluorescence of pyridine nucleotides monitored from the liver surface; however, the NADP+/NADPH ratio was decreased by sorbitol but tended to be increased by ethanol. Stimulation of drug metabolism by sorbitol was abolished by pretreatment of fasted rats with 6-aminonicotinamide, an inhibitor of the pentose phosphate shunt, but was not affected by aminooxyacetate, a transaminase inhibitor. These results indicate that sorbitol stimulated p-nitroanisole metabolism by providing NADPH via the pentose phosphate shunt. Ethanol and sorbitol caused changes in intracellular concentrations of NADPH in livers from fasted rats which correlated directly with changes in hepatic levels of citrate and aspartate. Furthermore, aspartate infusion reduced the inhibition of p-nitroanisole O-demethylation by ethanol. This inhibition was also reversed partially by sorbitol in livers from 6-aminonicotinamide-treated rats. It is concluded that ethanol inhibits mixed-function oxidation primarily by decreasing the concentrations of citric acid cycle intermediates which leads to depletion of cytosolic NADPH.
在禁食且经苯巴比妥处理的大鼠的灌注肝脏中，山梨醇和乙醇对对硝基苯甲醚O - 去甲基化具有相反的作用。山梨醇（2 mM）使药物代谢增强50%，而乙醇（20 mM）导致80%的抑制。山梨醇和乙醇灌注均降低了NAD⁺/NADH比值，并增加了从肝脏表面监测到的吡啶核苷酸荧光；然而，山梨醇使NADP⁺/NADPH比值降低，而乙醇则使其趋于升高。用磷酸戊糖途径抑制剂6 - 氨基烟酰胺预处理禁食大鼠后，山梨醇对药物代谢的刺激作用被消除，但不受转氨酶抑制剂氨基氧乙酸的影响。这些结果表明，山梨醇通过磷酸戊糖途径提供NADPH来刺激对硝基苯甲醚的代谢。乙醇和山梨醇引起禁食大鼠肝脏中NADPH细胞内浓度的变化，这与肝脏中柠檬酸和天冬氨酸水平的变化直接相关。此外，输注天冬氨酸可减轻乙醇对对硝基苯甲醚O - 去甲基化的抑制作用。在经6 - 氨基烟酰胺处理的大鼠肝脏中，山梨醇也可部分逆转这种抑制作用。结论是，乙醇主要通过降低柠檬酸循环中间产物的浓度来抑制混合功能氧化，这导致胞质NADPH耗竭。
