Ma Xiaochao, Idle Jeffrey R, Malfatti Michael A, Krausz Kristopher W, Nebert Daniel W, Chen Chong-Sheng, Felton James S, Waxman David J, Gonzalez Frank J
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, Bethesda, MD 20892, USA.
Carcinogenesis. 2007 Mar;28(3):732-7. doi: 10.1093/carcin/bgl184. Epub 2006 Oct 19.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) carcinogenesis is initiated by N(2)-hydroxylation, mediated by several cytochromes P450, including CYP1A1. However, the role of CYP1A1 in PhIP metabolic activation in vivo is unclear. In this study, Cyp1a1-null and wild-type (WT) mice were used to investigate the potential role of CYP1A1 in PhIP metabolic activation in vivo. PhIP N(2)-hydroxylation was actively catalyzed by lung homogenates of WT mice, at a rate of 14.9 +/- 5.0 pmol/min/g tissue, but <1 pmol/min/g tissue in stomach and small intestine, and almost undetectable in mammary gland and colon. PhIP N(2)-hydroxylation catalyzed by lung homogenates of Cyp1a1-null mice was approximately 10-fold lower than that of WT mice. In contrast, PhIP N(2)-hydroxylation activity in lung homogenates of Cyp1a2-null versus WT mice was not decreased. Pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin increased lung Cyp1a1 mRNA and lung homogenate PhIP N(2)-hydroxylase activity approximately 50-fold in WT mice, where the activity was substantially inhibited (70%) by monoclonal antibodies against CYP1A1. In vivo, 30 min after oral treatment with PhIP, PhIP levels in lung were similar to those in liver. After a single dose of 0.1 mg/kg [(14)C]PhIP, lung PhIP-DNA adduct levels in Cyp1a1-null mice, but not in Cyp1a2-null mice, were significantly lower (P = 0.0028) than in WT mice. These results reveal that mouse lung has basal and inducible PhIP N(2)-hydroxylase activity predominantly catalyzed by CYP1A1. Because of the high inducibility of human CYP1A1, especially in cigarette smokers, the role of lung CYP1A1 in PhIP carcinogenesis should be considered. (237 words).
2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）致癌作用始于N(2)-羟基化，由包括CYP1A1在内的几种细胞色素P450介导。然而，CYP1A1在体内PhIP代谢活化中的作用尚不清楚。在本研究中，使用Cyp1a1基因敲除小鼠和野生型（WT）小鼠来研究CYP1A1在体内PhIP代谢活化中的潜在作用。WT小鼠肺匀浆可积极催化PhIP的N(2)-羟基化，速率为14.9±5.0 pmol/分钟/克组织，但胃和小肠中的速率<1 pmol/分钟/克组织，在乳腺和结肠中几乎检测不到。Cyp1a1基因敲除小鼠肺匀浆催化的PhIP N(2)-羟基化比WT小鼠低约10倍。相比之下，Cyp1a2基因敲除小鼠与WT小鼠肺匀浆中的PhIP N(2)-羟基化活性没有降低。用2,3,7,8-四氯二苯并对二恶英预处理可使WT小鼠肺Cyp1a1 mRNA和肺匀浆PhIP N(2)-羟化酶活性增加约50倍，其中该活性被抗CYP1A1单克隆抗体显著抑制（70%）。在体内，用PhIP口服治疗30分钟后，肺中的PhIP水平与肝脏中的相似。单次给予0.1 mg/kg [(14)C]PhIP后，Cyp1a1基因敲除小鼠肺中的PhIP-DNA加合物水平显著低于WT小鼠（P = 0.0028），而Cyp1a2基因敲除小鼠则不然。这些结果表明，小鼠肺具有主要由CYP1A1催化的基础和诱导性PhIP N(2)-羟化酶活性。由于人类CYP1A1具有高诱导性，尤其是在吸烟者中，应考虑肺CYP1A1在PhIP致癌作用中的作用。 （237字）
