James R, Desmond P, Küpfer A, Schenker S, Branch R A
J Pharmacol Exp Ther. 1981 Apr;217(1):127-32.
Rats were pretreated with allyl alcohol, carbon tetrachloride or bromobenzene to induce histopathological evidence of periportal, midzonal to centrilobular, and centrilobular hepatic necrosis. The amount of various drug metabolizing enzyme systems present after necrosis was determined indirectly by measuring the rate of metabolism for specific substrates in vitro. The chemically induced hepatocellular injury of these toxins produced variable but significant alterations in hepatic drug metabolism. The changes in enzymatic activity related well with the area of the lesion produced by each toxin. Thus, these hepatotoxins appear to be useful as probes to determine the hepatolobular distribution of the various drug metabolizing enzyme systems studied. Aniline hydroxylase and p-nitroanisole o-demethylase were concentrated in the midzonal and periportal zones, while aminopyrine N-demethylase was more uniformly distributed along the cytochrome P-450 gradient. Glucuronyltransferase was more heavily concentrated in the periportal-midzonal area, acetyltransferase was centrilobular-midzonal and glutathionetransferase was concentrated in the midzonal region. Thus, as is the case for cytochrome P-450, there appears to be a high degree of regional organization for all of the drug metabolizing enzymes within the hepatic lobule.
用烯丙醇、四氯化碳或溴苯对大鼠进行预处理，以诱导门静脉周围、中区至小叶中心以及小叶中心性肝坏死的组织病理学证据。坏死发生后，通过体外测量特定底物的代谢速率间接测定存在的各种药物代谢酶系统的量。这些毒素化学诱导的肝细胞损伤在肝脏药物代谢中产生了可变但显著的改变。酶活性的变化与每种毒素产生的病变区域密切相关。因此，这些肝毒素似乎可用作探针，以确定所研究的各种药物代谢酶系统在肝小叶中的分布。苯胺羟化酶和对硝基苯甲醚O-脱甲基酶集中在中区和门静脉周围区域，而氨基比林N-脱甲基酶沿细胞色素P-450梯度分布更为均匀。葡糖醛酸转移酶在门静脉周围-中区区域更为集中，乙酰转移酶在小叶中心-中区，谷胱甘肽转移酶集中在中区区域。因此，与细胞色素P-450的情况一样，肝小叶内所有药物代谢酶似乎都存在高度的区域组织化。
