Prescott L F
Clinical Pharmacology, University of Edinburgh, Edinburgh, UK.
Br J Clin Pharmacol. 2000 Apr;49(4):291-301. doi: 10.1046/j.1365-2125.2000.00167.x.
It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with 'therapeutic intent' had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol-alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic. The paracetamol-alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short-lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol-ethanol interaction is not specific for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical. In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the first few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insufficient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestion-ingly accepted this supposed interaction in man for so long with such scant regard for scientific objectivity.
据称，慢性酒精中毒者不仅在过量服用对乙酰氨基酚（扑热息痛）时，而且在其治疗性使用时，发生对乙酰氨基酚肝毒性的风险都会增加。易感性增加被认为是由于乙醇诱导肝微粒体酶，导致对乙酰氨基酚的有毒代谢物形成增加。然而，支持这些说法的临床证据只是传闻，而且在非慢性酒精中毒患者中，过量服用后也会出现同样的肝损伤。许多据称在“治疗目的”服用对乙酰氨基酚后出现肝损伤的酒精中毒患者，显然服用了大量过量药物。尚未进行适当的临床研究来调查所谓的对乙酰氨基酚与酒精的相互作用，而且从未通过给慢性酒精中毒者服用治疗剂量的对乙酰氨基酚作为激发试验来引发急性肝损伤。对乙酰氨基酚与酒精的相互作用很复杂；急性和慢性乙醇有相反的作用。在动物中，慢性乙醇会导致肝微粒体酶的诱导，并如预期的那样增加对乙酰氨基酚的肝毒性（乙醇主要诱导CYP2E1，该同工酶在对乙酰氨基酚的氧化代谢中很重要）。然而，在人类中，长期饮酒只会引起CYP2E1适度（约两倍）且短暂的诱导，并且对乙酰氨基酚的有毒代谢活化没有相应增加（如所声称的那样）。对乙酰氨基酚与乙醇的相互作用并非针对细胞色素P450的任何一种同工酶具有特异性，而且似乎除CYP2E1之外的同工酶主要负责人类中对乙酰氨基酚的氧化代谢。急性乙醇在动物和人类中均抑制对乙酰氨基酚的微粒体氧化。这在动物中可防止肝损伤，并且有证据表明在人类中也是如此。当乙醇消除后，保护作用消失，乙醇和对乙酰氨基酚摄入的相对时间很关键。在许多声称慢性酒精中毒者中对乙酰氨基酚肝毒性增强的报告中，情况可能正好相反，因为酒精实际上是与对乙酰氨基酚同时服用的。慢性酒精中毒者在戒断的头几天可能最易受到对乙酰氨基酚毒性作用的影响，但此时给予最大治疗剂量对肝功能检查没有不良影响。尽管长期饮酒确实可能增加人类中对乙酰氨基酚肝毒性的风险（可能是通过损害谷胱甘肽合成），但没有足够的证据支持所谓的主要毒性相互作用。令人惊讶的是，临床医生和其他人如此长时间毫无质疑地接受了人类中这种所谓的相互作用，而对科学客观性如此漠视。
