Hook G E, Haseman J K, Lucier G W
Chem Biol Interact. 1975 Mar;10(3):199-214. doi: 10.1016/0009-2797(75)90113-1.
The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on a number of hepatic and extrahepatic foreign-compound-metabolizing enzyme systems in microsomes from rats, rabbits and guinea pigs were investigated. Following TCDD treatment, the N-demethylation of benzphetamine, aminopyrine and ethylmorphine was suppressed in hepatic microsomes from male but not from female rats. However, both cytochrome P-450 and benzpyrene hydroxylase were significantly stimulated in hepatic microsomes from both male and female rats at doses as small as 1 mug TCDD/kg body weight. The inductive effect on rat hepatic microsomal enzymes was considerably more persistent than the suppressive effect. Following a single oral dose of 25 mug TCDD/kg weight, benzpyrene hydroxylase of male rat liver microsomes remained significantly elevated for 73 days but the suppression of benzphetamine N-demethylase had gone after 35 days. The induction of benzpyrene hydroxylase in male rat liver microsomes by TCDD was independent of the age of the rat and the levels to which this enzyme was increased was similar in male rats of all ages. However, the suppression of benzphetamine N-demethylase in male rat liver microsomes was age related: the suppression was seen only in adult animals and in the very young (10 days old) the enzyme was actually induced by TCDD. Inductive effects appeared in both smooth and rough-surfaced hepatic microsomes from male rats but the suppression of N-demethylation occurred only in the smooth-surfaced microsomes (SER). In microsomes from extrahepatic tissues of the rat, induction of mixed-function oxidases (MFOs) by TCDD occurred only in the kidney. However, UDPglucuronyltransferase was induced in microsomes from lung, kidney, intestine and brain but not testes. The response in the rabbit and guinea pig to TCDD differed considerably from that in the rat. Benzpyrene hydroxylase was unaffected in hepatic microsomes from the guinea pig and actually suppressed in microsomes from rabbit liver. Benzphetamine N-demethylase was also suppressed in rabbit liver microsomes. Glucuronyl-transferase was unaffected by TCDD in microsomes from liver, lung or kidney of the rabbit and guinea pig. The only lung enzyme responsive to TCDD was biphenyl 4-hydroxylase of the rabbit and guinea pig. Suppression was not observed in any of the extraheptic tissues studied and may be confined to only certain hepatic systems.
研究了2,3,7,8-四氯二苯并-对-二噁英（TCDD）对大鼠、兔子和豚鼠微粒体中多种肝内和肝外外源化合物代谢酶系统的影响。给予TCDD处理后，雄性大鼠肝微粒体中苄非他明、氨基比林和N-脱甲基酶的N-脱甲基作用受到抑制，而雌性大鼠则未受影响。然而，在给予低至1μg TCDD/kg体重的剂量时，雄性和雌性大鼠肝微粒体中的细胞色素P-450和苯并芘羟化酶均受到显著刺激。TCDD对大鼠肝微粒体酶的诱导作用比抑制作用持续时间长得多。单次口服25μg TCDD/kg体重后，雄性大鼠肝微粒体中的苯并芘羟化酶在73天内仍显著升高，但苄非他明N-脱甲基酶的抑制作用在35天后消失。TCDD对雄性大鼠肝微粒体中苯并芘羟化酶的诱导作用与大鼠年龄无关，所有年龄段雄性大鼠该酶的升高水平相似。然而，雄性大鼠肝微粒体中苄非他明N-脱甲基酶的抑制作用与年龄有关：仅在成年动物中观察到抑制作用，而在非常年幼（10日龄）的动物中，该酶实际上被TCDD诱导。诱导作用在雄性大鼠的光滑和粗糙表面肝微粒体中均出现，但N-脱甲基作用的抑制仅发生在光滑表面微粒体（滑面内质网）中。在大鼠肝外组织的微粒体中，TCDD仅在肾脏中诱导混合功能氧化酶（MFOs）。然而，UDP-葡萄糖醛酸基转移酶在肺、肾、肠和脑的微粒体中被诱导，但在睾丸中未被诱导。兔子和豚鼠对TCDD的反应与大鼠有很大不同。豚鼠肝微粒体中的苯并芘羟化酶未受影响，而兔子肝微粒体中的该酶实际上受到抑制。兔子肝微粒体中的苄非他明N-脱甲基酶也受到抑制。TCDD对兔子和豚鼠肝、肺或肾微粒体中的葡萄糖醛酸基转移酶无影响。兔子和豚鼠肺中唯一对TCDD有反应的酶是联苯4-羟化酶。在所研究的任何肝外组织中均未观察到抑制作用，且抑制作用可能仅限于某些肝内系统。
