Larrey D, Berson A, Habersetzer F, Tinel M, Castot A, Babany G, Lettéron P, Freneaux E, Loeper J, Dansette P
Unité de Recherches de Physiopathologie Hépatique (INSERM U24), Hôpital Beaujon, Clichy, France.
Hepatology. 1989 Aug;10(2):168-73. doi: 10.1002/hep.1840100208.
Amineptine-induced immunoallergic hepatitis is unpredictable. It may be related to its oxidation into a reactive metabolite acting as hapten. We have looked for a possible genetic predisposition involving drug oxidation capacity and/or cell defense mechanisms in nine patients with previous amineptine hepatitis. Drug oxidation capacity was assessed using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. The eight patients tested had the extensive metabolizer phenotype. The susceptibility to amineptine metabolites was studied by an in vitro test assessing the destruction of the patients' lymphocytes by reactive metabolites generated from amineptine by a standardized oxidation microsomal system. Lymphocyte death increased with the dose of amineptine (1 to 2.5 mM); it was increased by preincubation with trichloropropene oxide, but was absent when amineptine was omitted or when the oxidation system was not operating. Mean lymphocyte death was twice higher in the nine patients with amineptine hepatitis than in 17 healthy controls. In contrast, when the test was performed with acetaminophen (3 to 10 mM), lymphocyte death was similar in controls and in patients. Basal epoxide hydrolase activity toward benzo[a]pyrene-4,5-oxide and glutathione concentration was similar in lymphocytes from controls and patients. Family studies showed an increased susceptibility to amineptine metabolites in lymphocytes from several first-degree relatives of two patients. These results show that amineptine hepatitis occurs in patients with extensive dextromethorphan oxidation capacity but with an increased susceptibility to amineptine reactive metabolites, probably related to a genetic deficiency in a cell defense mechanism.
阿米奈丁诱发的免疫过敏性肝炎不可预测。这可能与其氧化成作为半抗原的反应性代谢物有关。我们在9例曾患阿米奈丁肝炎的患者中寻找可能涉及药物氧化能力和/或细胞防御机制的遗传易感性。使用右美沙芬评估药物氧化能力，右美沙芬是一种最近被提议作为异喹胍替代物的测试化合物。接受测试的8例患者具有广泛代谢型。通过体外试验研究对阿米奈丁代谢物的易感性，该试验评估由标准化氧化微粒体系统从阿米奈丁产生的反应性代谢物对患者淋巴细胞的破坏作用。淋巴细胞死亡随阿米奈丁剂量（1至2.5 mM）增加而增加；用三氯丙烯氧化物预孵育可使其增加，但省略阿米奈丁或氧化系统不运行时则无此现象。9例阿米奈丁肝炎患者的平均淋巴细胞死亡率是17例健康对照者的两倍。相反，当用对乙酰氨基酚（3至10 mM）进行测试时，对照者和患者的淋巴细胞死亡率相似。对照组和患者淋巴细胞中对苯并[a]芘 - 4,5 - 氧化物的基础环氧化物水解酶活性和谷胱甘肽浓度相似。家族研究显示，两名患者的几名一级亲属的淋巴细胞对阿米奈丁代谢物的易感性增加。这些结果表明，阿米奈丁肝炎发生在右美沙芬氧化能力广泛但对阿米奈丁反应性代谢物易感性增加的患者中，这可能与细胞防御机制中的遗传缺陷有关。
