Skoulis N P, James R C, Harbison R D, Roberts S M
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205.
Toxicol Appl Pharmacol. 1989 Jun 1;99(1):139-47. doi: 10.1016/0041-008x(89)90119-1.
The ability of morphine and other opioid analgesic drugs to diminish hepatocellular glutathione (GSH) concentrations was examined in ICR mice. When administered intraperitoneally, morphine, hydromorphone, ethylmorphine, l-alpha-acetylmethadol (LAAM), and meperidine all caused a significant decrease in hepatic GSH concentrations in male mice while codeine, methadone, butorphanol, nalbuphine, and pentazocine were without effect even at doses up to those approaching acute lethality. Depression of hepatic GSH equivalent to that observed after ip administration could be elicited by icv administration of small doses of morphine, ethylmorphine, and hydromorphone. LAAM and meperidine were ineffective following icv administration in these experiments. The discrepancy between results following ip versus icv administration of LAAM and meperidine suggests that hepatic metabolism of some opioids may be important for their activity in the CNS, as both norLAAM and normeperidine diminished hepatic GSH when administered by the icv route. The opioid-induced lowering of hepatic GSH does not appear to be sex-dependent since morphine and LAAM produced qualitatively and quantitatively similar effects on hepatic GSH in female mice. Morphine administered icv produced a substantial increase in the hepatotoxicity of two compounds dependent upon GSH for detoxification, acetaminophen and cocaine, as measured by serum alanine aminotransferase activities. These observations indicate that a number of opioid analgesic drugs have the potential to diminish hepatic GSH. Further, these results support earlier studies which indicate that central opioid effects on hepatic GSH are mediated through mu-opioid receptor stimulation. Last, these studies suggest that a centrally initiated opioid action on hepatic GSH may significantly influence the susceptibility of the liver to the effects of some hepatotoxic agents.
在ICR小鼠中检测了吗啡及其他阿片类镇痛药降低肝细胞谷胱甘肽（GSH）浓度的能力。腹腔注射时，吗啡、氢吗啡酮、乙基吗啡、左旋-α-乙酰美沙多（LAAM）和哌替啶均可使雄性小鼠肝脏GSH浓度显著降低，而可待因、美沙酮、布托啡诺、纳布啡和喷他佐辛即使在接近急性致死剂量时也无此作用。小剂量吗啡、乙基吗啡和氢吗啡酮脑室内注射可引起与腹腔注射后观察到的肝脏GSH降低程度相当的情况。在这些实验中，LAAM和哌替啶脑室内注射无效。LAAM和哌替啶腹腔注射与脑室内注射结果的差异表明，某些阿片类药物的肝脏代谢可能对其在中枢神经系统中的活性很重要，因为脑室内注射去甲LAAM和去甲哌替啶时均可降低肝脏GSH。阿片类药物诱导的肝脏GSH降低似乎与性别无关，因为吗啡和LAAM对雌性小鼠肝脏GSH产生了定性和定量相似的影响。脑室内注射吗啡可使两种依赖GSH解毒的化合物对乙酰氨基酚和可卡因的肝毒性显著增加，这通过血清丙氨酸转氨酶活性来衡量。这些观察结果表明，许多阿片类镇痛药有降低肝脏GSH的潜力。此外，这些结果支持了早期的研究，即中枢阿片类药物对肝脏GSH的影响是通过μ-阿片受体刺激介导的。最后，这些研究表明，中枢引发的阿片类药物对肝脏GSH的作用可能会显著影响肝脏对某些肝毒性药物作用的易感性。
