Boobis A R, Gooderham N J, Rich K J, Zhao K, Edwards R J, Murray B P, Lynch A M, Murray S, Davies D S
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, England.
Princess Takamatsu Symp. 1995;23:134-44.
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are amongst the most abundant of the heterocyclic aromatic amines formed during the cooking of beef. Both compounds are genotoxic and carcinogenic in rodents. These effects are manifested only after activation of the amines by P450. Human liver is very active at converting these amines to mutagenic products. Studies in vitro have established that, for both amines, mutagenicity with human liver microsomes is entirely via the N-hydroxylamine, essentially the only oxidation product of either amine. Both N-hydroxylation and mutagenicity of the amines can be almost completely inhibited by furafylline, a potent and highly selective inhibitor of CYP1A2 in man. These data, together with the work of others, show that the N-hydroxylation and hence the mutagenicity of both MeIQx and PhIP in man is catalyzed almost exclusively by CYP1A2. Liver from cynomolgus monkeys, unlike that from humans and marmosets, is very poor at activating MeIQx or PhIP to mutagenic products. Studies with anti-peptide antibodies of defined specificity revealed that this is due to the absence of CYP1A2, suggesting that this species should not be used to assess the possible risk posed to man by these amines. The marmoset would be a better species for this purpose.
2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）和2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）是牛肉烹饪过程中形成的最丰富的杂环芳香胺。这两种化合物在啮齿动物中具有遗传毒性和致癌性。这些作用只有在胺类被细胞色素P450激活后才会显现。人类肝脏在将这些胺类转化为诱变产物方面非常活跃。体外研究表明，对于这两种胺类，与人类肝脏微粒体的诱变性完全通过N-羟胺，基本上是这两种胺类唯一的氧化产物。胺类的N-羟基化和诱变性几乎可以被呋喃菲林完全抑制，呋喃菲林是人体内CYP1A2的一种强效且高度选择性的抑制剂。这些数据以及其他研究结果表明，在人体内，MeIQx和PhIP的N-羟基化以及由此产生的诱变性几乎完全由CYP1A2催化。食蟹猴的肝脏与人类和狨猴的肝脏不同，在将MeIQx或PhIP激活为诱变产物方面能力很差。使用具有特定特异性的抗肽抗体进行的研究表明，这是由于缺乏CYP1A2，这表明该物种不应用于评估这些胺类对人类可能造成的风险。狨猴在这方面会是一个更好的物种。
