Bhatt H S, Lober S B, Combes B
Department of Internal Medicine, University of Texas Health Science Center, Southwestern Medical School, Dallas 75235.
Biochem Pharmacol. 1988 Apr 15;37(8):1581-9. doi: 10.1016/0006-2952(88)90021-4.
In previous studies, diethylmaleate (DEM)- and phorone-induced hepatic glutathione (GSH) depletion in rats was accompanied by impaired evolution of 14CO2 from the N-14C-labeled methyl groups of aminopyrine, which in turn was attributed to impaired generation of formaldehyde, its subsequent oxidation to formate, or to some combination of both. In the present study, l-buthionine sulfoximine (BSO)-induced hepatic GSH depletion was also accompanied by decreased evolution of CO2 from aminopyrine, but the extent of the fall in CO2 was less than that induced by DEM or phorone, even though the decrease in hepatic GSH was comparable with all three GSH-lowering compounds. Incubation of freshly prepared normal hepatic microsomes in vitro with the GSH-lowering agents resulted in impaired aminopyrine-N-demethylase (APDM) activity with inhibition by phorone greater than DEM greater than BSO. By contrast, hepatic microsomes prepared from rats pretreated with these compounds had normal APDM activity. 14CO2 evolution from i.p. administered [14C]formaldehyde was not impaired by any of the GSH-lowering compounds. Thus, assessment of APDM activity and formaldehyde metabolism did not unequivocally establish the mechanism(s) by which CO2 evolution from aminopyrine is depressed by DEM, phorone and BSO, although low GSH is likely to impair metabolism of formaldehyde formed in liver after demethylation of aminopyrine. Quantitative differences in the degree of depression of CO2 evolution suggest that at least DEM and phorone exert an additional inhibitory effect by a GSH-independent mechanism. This may involve inhibition of aminopyrine-N-demethylase activity.
在先前的研究中，马来酸二乙酯（DEM）和佛尔酮诱导的大鼠肝脏谷胱甘肽（GSH）耗竭伴随着氨基比林N-14C标记甲基的14CO2生成受损，这反过来又归因于甲醛生成受损、其随后氧化为甲酸或两者的某种组合。在本研究中，L-丁硫氨酸亚砜胺（BSO）诱导的肝脏GSH耗竭也伴随着氨基比林CO2生成减少，但CO2下降的程度小于DEM或佛尔酮诱导的程度，尽管肝脏GSH的减少与所有三种降低GSH的化合物相当。用降低GSH的药物在体外孵育新鲜制备的正常肝脏微粒体导致氨基比林-N-脱甲基酶（APDM）活性受损，佛尔酮的抑制作用大于DEM大于BSO。相比之下，用这些化合物预处理的大鼠制备的肝脏微粒体具有正常的APDM活性。腹腔注射[14C]甲醛后的14CO2生成不受任何降低GSH的化合物影响。因此，尽管低GSH可能会损害氨基比林去甲基化后在肝脏中形成的甲醛的代谢，但对APDM活性和甲醛代谢的评估并未明确确定DEM、佛尔酮和BSO抑制氨基比林CO2生成的机制。CO2生成抑制程度的定量差异表明，至少DEM和佛尔酮通过一种不依赖GSH的机制发挥额外的抑制作用。这可能涉及抑制氨基比林-N-脱甲基酶活性。
