Rikans L E, Hornbrook K R, Cai Y
Department of Pharmacology, University of Oklahoma College of Medicine, Oklahoma City 73190.
Mech Ageing Dev. 1994 Oct 20;76(2-3):89-99. doi: 10.1016/0047-6374(94)91584-9.
Severity of liver damage 24 h after intraperitoneal administration of carbon tetrachloride (0.2 ml/kg) was evaluated in female Fischer 344 rats aged 5, 14 and 28 months, i.e. in young adulthood, middle age and old age. Carbon tetrachloride-induced hepatotoxicity, as judged by the leakage of hepatic enzymes into the bloodstream and the disappearance of hepatic microsomal cytochrome P450, was much less severe in old rats than in young-adult rats. For example, serum sorbitol dehydrogenase (SDH) activity following carbon tetrachloride administration was 680 mumol/min/l in old rats compared with 1710 mumol/min/l in young-adult rats, and the loss of hepatic cytochrome P450 was 25% of the total amount in old rats compared with 50% of the total in young-adult rats. Spin trapping and electron spin resonance (ESR) spectroscopy were utilized to measure the conversion of carbon tetrachloride to trichloromethyl radicals in vivo. This primary bioactivation step occurred at similar rates in female rats aged 5, 14 and 28 months. In addition, the total nonheme iron contents in livers of rats in the three age groups were similar. Thus, the age associated attenuation of carbon tetrachloride-induced hepatotoxicity was not explained on the basis of decreased bioactivation to reactive species or decreased availability of iron for promotion of lipid peroxidation. The results suggest that other factors are important determinants of age-associated changes in sensitivity to toxic chemicals.
在5、14和28月龄的雌性Fischer 344大鼠（即年轻成年、中年和老年大鼠）中，评估腹腔注射四氯化碳（0.2 ml/kg）24小时后肝损伤的严重程度。通过肝酶泄漏到血液中以及肝微粒体细胞色素P450消失来判断，四氯化碳诱导的肝毒性在老年大鼠中比年轻成年大鼠轻得多。例如，注射四氯化碳后老年大鼠血清山梨醇脱氢酶（SDH）活性为680 μmol/min/l，而年轻成年大鼠为1710 μmol/min/l，老年大鼠肝细胞色素P450的损失占总量的25%，而年轻成年大鼠为50%。利用自旋捕获和电子自旋共振（ESR）光谱法测量体内四氯化碳向三氯甲基自由基的转化。这一主要生物活化步骤在5、14和28月龄的雌性大鼠中以相似的速率发生。此外，三个年龄组大鼠肝脏中的总非血红素铁含量相似。因此，四氯化碳诱导的肝毒性随年龄的减弱不能基于对反应性物种的生物活化降低或促进脂质过氧化的铁的可用性降低来解释。结果表明，其他因素是与年龄相关的对有毒化学物质敏感性变化的重要决定因素。
