Burke M D, Prough R A, Mayer R T
Drug Metab Dispos. 1977 Jan-Feb;5(1):1-8.
Certain characteristics of ethoxyresorufin O-de-ethylation, as catalyzed by microsomes of liver, lung, and intestine of control and pretreated rats and hamsters, were studied. The results support previous suggestions that the reaction is catalyzed primarily by a 3-methyl-cholanthrene (MC)-inducible mono-oxygenase which has a 448-nm absorption maximum in the reduced-CO difference spectrum. Ethoxyresorufin exhibited a type I binding spectrum with liver microsomes from MC-induced rats, but there was no clear interaction with microsomes from control or phenobarbital (PB)-induced rats. Maximum MC-induction of type I binding and de-ethylase activity coincided with the appearance of a cytochrome P-450 spectrum whose absorption maximum was shifted to 448 nm. Low concentrations of alpha-naphthoflavone (ANF) or benzo[a]pyrene (BP) inhibited the de-ethylation with liver microsomes of MC-treated rats (150 approximately 10(-9)M) but not those of control rats. A kinetic analysis of BP inhibition of this reaction showed it to be competitive. Inhibition of the MC-induced liver microsomal reaction by low concentrations of BP or ANF diminished rapidly with time. MC-induced rat liver microsomal de-ethylation of ethoxyresorufin was less sensitive than the PB-induced reaction to inhibition by metyrapone or SKF 525-A (I50 approximately 10(-6) - 10(-4)M). However, microsomes from rat liver, lung, and intestine had very low constitutive activities (less than 0.1 nmol/min/mg of protein). MC greatly induced the de-ethylation reaction in liver (200 X), intestine (40 X) and lung (10 X). De-ethylation of ethoxyresorufin in microsomes from control and MC-induced rat lung was inhibited by low concentrations of either ANF or BP (I50 approximately 10(-8) M). Control hamster liver microsomes were several times more active in de-ethylation than control rat liver microsomes, but MC-induction of hamster liver was only 1/10 of that in rat liver. Control hamster lung activity was similar to that of control rat lung, but was not appreciably induced by MC.
研究了对照和预处理大鼠及仓鼠肝脏、肺和肠道微粒体催化的乙氧异吩恶唑酮O-脱乙基反应的某些特性。结果支持了先前的观点，即该反应主要由一种3-甲基胆蒽（MC）诱导的单加氧酶催化，该酶在还原型一氧化碳差光谱中的最大吸收峰为448nm。乙氧异吩恶唑酮与MC诱导的大鼠肝脏微粒体呈现I型结合光谱，但与对照或苯巴比妥（PB）诱导的大鼠微粒体无明显相互作用。I型结合和脱乙基酶活性的最大MC诱导与细胞色素P-450光谱的出现一致，其最大吸收峰移至448nm。低浓度的α-萘黄酮（ANF）或苯并[a]芘（BP）抑制MC处理大鼠肝脏微粒体的脱乙基反应（150约10⁻⁹M），但不抑制对照大鼠的反应。BP对该反应抑制作用的动力学分析表明其为竞争性抑制。低浓度的BP或ANF对MC诱导的肝脏微粒体反应的抑制作用随时间迅速减弱。MC诱导的大鼠肝脏微粒体乙氧异吩恶唑酮脱乙基反应比PB诱导的反应对甲吡酮或SKF 525-A的抑制作用更不敏感（I50约10⁻⁶ - 10⁻⁴M）。然而，大鼠肝脏、肺和肠道的微粒体组成活性非常低（小于0.1nmol/分钟/毫克蛋白质）。MC极大地诱导了肝脏（200倍）、肠道（40倍）和肺（10倍）中的脱乙基反应。低浓度的ANF或BP（I50约10⁻⁸M）抑制对照和MC诱导的大鼠肺微粒体中乙氧异吩恶唑酮的脱乙基反应。对照仓鼠肝脏微粒体的脱乙基活性比对照大鼠肝脏微粒体高几倍，但MC对仓鼠肝脏的诱导作用仅为大鼠肝脏的1/10。对照仓鼠肺的活性与对照大鼠肺相似，但MC对其诱导作用不明显。
