Species differences in the metabolism of xenobiotics by cytochrome P450 are critical in evaluating the use of experimental animals in studying toxic compounds relevant to human diseases. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which is produced by high-temperature cooking of fish and meat, is activated to become a carcinogen by cytochrome P4501A2 (CYP1A2) through N²-hydroxylation in humans, but is detoxified by Cyp1a2 through 4′-hydroxylation in mice. CYP1A-humanized (hCYP1A) mice, in which mouse Cyp1a is replaced with human CYP1A, show constitutive human xenobiotic metabolism by hCYP1A, thereby serving as a suitable model for studying PhIP. Previous studies have demonstrated that oral administration of PhIP induces colon tumors in hCYP1A mice; however, these studies used a super-high dose, raising concerns regarding the relevance of the mechanism to human cancer. Herein, we systematically investigated PhIP-induced colon carcinogenesis in hCYP1A mice treated with lower doses. We found that a dose 2000 times lower than that used previously, which is comparable to human daily intake levels, could induce colon tumors, albeit at a lower incidence rate. We further investigated the transcriptome changes in the colon of hCYP1A mice treated with PhIP and identified that PhIP treatment increased the expression of Bax, Btg2, Ccng1, Cdkn1a, and Trp53inp1 and decreased the expression of Igf1 and Ccnd1. Since these genes are key components of the p53-dependent DNA damage response, the altered expression patterns indicated PhIP-induced DNA damage in hCYP1A mice. Together, these results prove that hCYP1A mice are suitable for studying PhIP-induced carcinogenesis and show that PhIP is an important colorectal cancer carcinogen in human diet.

中文翻译：

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膳食致癌物 PhIP 激活 CYP1A 人源化小鼠结肠中 p53 依赖性 DNA 损伤反应

细胞色素 P450 对异生物质代谢的物种差异对于评估实验动物在研究与人类疾病相关的有毒化合物中的用途至关重要。鱼肉高温蒸煮产生的2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）被细胞色素P4501A2（CYP1A2）通过N ^2-羟基化在人类中，但在小鼠中通过 4'-羟基化被 Cyp1a2 解毒。CYP1A 人源化 (hCYP1A) 小鼠，其中小鼠Cyp1a被人类CYP1A取代，显示 hCYP1A 的组成型人类外源性代谢，从而作为研究 PhIP 的合适模型。以前的研究表明，口服 PhIP 会在 hCYP1A 小鼠中诱发结肠肿瘤。然而，这些研究使用了超高剂量，引发了人们对该机制与人类癌症相关性的担忧。在此，我们系统地研究了低剂量处理的 hCYP1A 小鼠中 PhIP 诱导的结肠癌发生。我们发现，比以前使用的剂量低 2000 倍的剂量（与人类每日摄入量相当）可以诱发结肠肿瘤，尽管发病率较低。我们进一步研究了用 PhIP 处理的 hCYP1A 小鼠结肠中的转录组变化，发现 PhIP 处理增加了Bax、Btg2的表达, Ccng1 , Cdkn1a和Trp53inp1并降低Igf1和Ccnd1的表达。由于这些基因是 p53 依赖性 DNA 损伤反应的关键组成部分，因此改变的表达模式表明在 hCYP1A 小鼠中 PhIP 诱导的 DNA 损伤。总之，这些结果证明hCYP1A小鼠适合研究PhIP诱导的致癌作用，并表明PhIP是人类饮食中重要的结直肠癌致癌物。