HUMAN CYTOCHROME P-450PA (P-450IA2), THE PHENACETIN O-DEETHYLASE, IS PRIMARILY RESPONSIBLE FOR THE HEPATIC 3-DEMETHYLATION OF CAFFEINE AND N-OXIDATION OF CARCINOGENIC ARYLAMINES - (AROMATIC-AMINES HETEROCYCLIC AMINES CARCINOGEN METABOLISM)
HUMAN CYTOCHROME P-450PA (P-450IA2), THE PHENACETIN O-DEETHYLASE, IS PRIMARILY RESPONSIBLE FOR THE HEPATIC 3-DEMETHYLATION OF CAFFEINE AND N-OXIDATION OF CARCINOGENIC ARYLAMINES - (AROMATIC-AMINES HETEROCYCLIC AMINES CARCINOGEN METABOLISM)
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DOI：
10.1073/pnas.86.20.7696
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发表时间：
1989-10-01
影响因子：
11.1
通讯作者：
KADLUBAR, FF
中科院分区：
文献类型：
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作者：
BUTLER, MA;IWASAKI, M;KADLUBAR, FF
芳香胺是众所周知的职业致癌物，存在于熟食、烟草烟雾、合成燃料和农业化学品中。对于伯芳胺，肝细胞色素P-450的代谢N-氧化通常被认为是导致致癌的初始活化步骤。4-氨基联苯、2-萘胺和几种杂环胺的代谢活化最近已被证明可被大鼠细胞色素P-450 ISF-G及其人类直向同源物细胞色素P-450 PA催化。我们现在报告，人肝微粒体咖啡因3-去甲基化，在人类咖啡因生物转化的最初的主要步骤，是选择性催化细胞色素P-450 PA。从22例人体器官捐献者获得的肝微粒体制备物中，咖啡因3-去甲基化与4-氨基联苯N-氧化高度相关（r = 0.99; P < 0.0005），选择性抑制剂7，8-苯甲酮也同样降低了这两种活性。微粒体咖啡因3-去甲基化、4-氨基联苯N-氧化和非那西丁O-去乙基化的速率也彼此显著相关，并与免疫反应性人细胞色素P-450 PA的水平显著相关。此外，一种抗人细胞色素P-450 PA的兔多克隆抗体显示出强烈抑制所有这三种活性，并抑制致癌物2-萘胺和杂环胺、2-氨基-6-甲基二吡啶并[1，2-a：3“，2”-d]咪唑和2-氨基-3-甲基咪唑并[4，5-f]喹啉的N-氧化。人肝细胞色素P-450 PA也被证明可以催化咖啡因3-去甲基化、4-氨基联苯N-氧化和非那西丁O-去乙基化。因此，估计咖啡因3-去甲基化活性在人类中可能是有用的芳胺N-氧化表型的表征和评估是否肝细胞色素P-450 PA的水平，受环境或遗传因素的影响，有助于个体间差异的芳胺诱导的癌症的易感性。
Aromatic amines are well known as occupational carcinogens and are found in cooked foods, tobacco smoke, synthetic fuels, and agricultural chemicals. For the primary arylamines, metabolic N-oxidation by hepatic cytochromes P-450 is generally regarded as an initial activation step leading to carcinogenesis. The metabolic activation of 4-aminobiphenyl, 2-napththylamine, and several heterocyclic amines has been shown recently to be catalyzed by rat cytochrome P-450ISF-G and by its human ortholog, cytochrome P-450PA. We now report that human hepatic microsomal caffeine 3-demethylation, the initial major step in caffeine biotransformation in humans, is selectively catalyzed by cytochrome P-450PA. Caffeine 3-demethylation was highly correlated with 4-aminobiphenyl N-oxidation (r = 0.99; P < 0.0005) in hepatic microsomal preparations obtained from 22 human organ donors, and both activities were similarly decreased by the selective inhibitor, 7,8-benzoflavone. The rates of microsomal caffeine 3-demethylation, 4-aminobiphenyl N-oxidation, and phenacetin O-deethylation were also significantly correlated with each other and with the levels of immunoreactive human cytochrome P-450PA. Moreover, a rabbit polyclonal antibody raised to human cytochrome P-450PA was shown to inhibit strongly all three of these activities and to inhibit the N-oxidation of the carcinogen 2-naphthylamine and the heterocyclic amines, 2-amino-6-methyldipyrido[1,2-a:3'',2''-d]imidazole and 2-amino-3-methylimidazo[4,5-f]-quinoline. Human liver cytochrome P-450PA was also shown to catalyze caffeine 3-demethylation, 4-aminobiphenyl N-oxidation, and phenacetin O-deethylation. Thus, estimation of caffeine 3-demethylation activity in humans may be useful in the characterization of arylamine N-oxidation phenotypes and in the assessment of whether or not the hepatic levels of cytochrome P-450PA, as affected by environmental or genetic factors, contribute to interindividual differences in susceptibility to arylamine-induced cancers.