Culo F, Renić M, Sabolović D, Rados M, Bilić A, Jagić V
Department of Physiology and Immunology, School of Medicine, Zagreb, Croatia.
Eur J Gastroenterol Hepatol. 1995 Aug;7(8):757-62.
To investigate the effect of ketoconazole on acetaminophen (AAP)-induced hepatotoxicity in mice.
Mice were given AAP intragastrically (300 mg/kg) and treated with ketoconazole (100 mg/kg intraperitoneally) or saline either 30 min before or 2-3 h after AAP administration. Mortality was recorded for 48 h, during which all mice given saline either died or recovered fully. Serum alanine and aspartate transaminase levels were determined 24 h after administration of AAP. Prostaglandin E2, thromboxane A2 and leukotriene C4 production was determined 6 h after AAP administration in the supernatants from the short-term culture of liver fragments by radioimmunoassay.
Ketoconazole significantly decreased mortality and transaminase levels when given to mice either 30 min before or 2 h after AAP. Liver fragments from mice with AAP hepatitis produced greater quantities of prostaglandin E2, thromboxane A2 and leukotriene C4 than fragments from normal liver. Pretreatment of mice with ketoconazole or its addition to liver fragments ex vivo further increased the production of prostaglandin E2 and reduced the production of thromboxane A2. The effect of ketoconazole on leukotriene C4 synthesis was different in vivo (synthesis stimulation) from in vitro (synthesis inhibition).
The protective effect of ketoconazole in AAP hepatitis is most probably mediated by modulation of eicosanoid synthesis by liver cells.
研究酮康唑对乙酰氨基酚（AAP）诱导的小鼠肝毒性的影响。
给小鼠灌胃AAP（300mg/kg），并在AAP给药前30分钟或给药后2 - 3小时腹腔注射酮康唑（100mg/kg）或生理盐水。记录48小时内的死亡率，在此期间，所有给予生理盐水的小鼠要么死亡，要么完全恢复。在给予AAP 24小时后测定血清丙氨酸和天冬氨酸转氨酶水平。通过放射免疫测定法在肝组织块短期培养上清液中测定AAP给药6小时后前列腺素E2、血栓素A2和白三烯C4的生成量。
当在AAP给药前30分钟或给药后2小时给予小鼠酮康唑时，酮康唑显著降低了死亡率和转氨酶水平。AAP肝炎小鼠的肝组织块比正常肝脏组织块产生更多的前列腺素E2、血栓素A2和白三烯C4。用酮康唑预处理小鼠或在体外将其添加到肝组织块中，可进一步增加前列腺素E2的生成并减少血栓素A2的生成。酮康唑对白三烯C4合成的影响在体内（合成刺激）和体外（合成抑制）有所不同。
酮康唑在AAP肝炎中的保护作用很可能是通过调节肝细胞类花生酸的合成来介导的。
