Anderson K E, Hammons G J, Kadlubar F F, Potter J D, Kaderlik K R, Ilett K F, Minchin R F, Teitel C H, Chou H C, Martin M V, Guengerich F P, Barone G W, Lang N P, Peterson L A
Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis 55454, USA.
Carcinogenesis. 1997 May;18(5):1085-92. doi: 10.1093/carcin/18.5.1085.
Epidemiologic studies have suggested that aromatic amines (and nitroaromatic hydrocarbons) may be carcinogenic for human pancreas. Pancreatic tissues from 29 organ donors (13 smokers, 16 non-smokers) were examined for their ability to metabolize aromatic amines and other carcinogens. Microsomes showed no activity for cytochrome P450 (P450) 1A2-dependent N-oxidation of 4-aminobiphenyl (ABP) or for the following activities (and associated P450s): aminopyrine N-demethylation and ethylmorphine N-demethylation (P450 3A4); ethoxyresorufin O-deethylation (P450 1A1) and pentoxyresorufin O-dealkylation (P450 2B6); p-nitrophenol hydroxylation and N-nitrosodimethyl-amine N-demethylation (P450 2E1); lauric acid omega-hydroxylation (P450 4A1); and 4-(methylnitrosamino)-1-(3-pyridyl-1-butanol) (NNAL) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) alpha-oxidation (P450 1A2, 2A6, 2D6). Antibodies were used to examine microsomal levels of P450 1A2, 2A6, 2C8/9/18/19, 2E1, 2D6, and 3A3/4/5/7 and epoxide hydrolase. Immunoblots detected only epoxide hydrolase at low levels; P450 levels were <1% of liver. Microsomal benzidine/prostaglandin hydroperoxidation activity was low. In pancreatic cytosols and microsomes, 4-nitrobiphenyl reductase activities were present at levels comparable to human liver. The O-acetyltransferase activity (AcCoA-dependent DNA-binding of [3H]N-hydroxy-ABP) of pancreatic cytosols was high, about twothirds the levels measured in human colon. Cytosols showed high activity for N-acetylation of p-aminobenzoic acid, but not of sulfamethazine, indicating that acetyltransferase-1 (NAT1) is predominantly expressed in this tissue. Cytosolic sulfotransferase was detected at low levels. Using 32P-post-labeling enhanced by butanol extraction, putative arylamine-DNA adducts were detected in most samples. Moreover, in eight of 29 DNA samples, a major adduct was observed that was chromatographically identical to the predominant ABP-DNA adduct, N-(deoxyguanosin-8-yl)-ABP. These results are consistent with a hypothesis that aromatic amines and nitroaromatic hydrocarbons may be involved in the etiology of human pancreatic cancer.
流行病学研究表明，芳香胺（和硝基芳烃）可能对人类胰腺具有致癌性。对29名器官捐献者（13名吸烟者，16名非吸烟者）的胰腺组织进行了检测，以评估其代谢芳香胺和其他致癌物的能力。微粒体对细胞色素P450（P450）1A2依赖性的4-氨基联苯（ABP）N-氧化反应以及以下活性（和相关的P450）均无活性：氨基比林N-去甲基化和乙基吗啡N-去甲基化（P450 3A4）；乙氧基异吩恶唑酮O-脱乙基化（P450 1A1）和戊氧基异吩恶唑酮O-脱烷基化（P450 2B6）；对硝基苯酚羟基化和N-亚硝基二甲胺N-去甲基化（P450 2E1）；月桂酸ω-羟基化（P450 4A1）；以及4-（甲基亚硝基氨基）-1-（3-吡啶基）-1-丁醇（NNAL）和4-（甲基亚硝基氨基）-1-（3-吡啶基）-1-丁酮（NNK）α-氧化反应（P450 1A2、2A6、2D6）。使用抗体检测微粒体中P450 1A2、2A6、2C8/9/18/19、2E1、2D6以及3A3/4/5/7和环氧化物水解酶的水平。免疫印迹仅检测到低水平的环氧化物水解酶；P450水平低于肝脏的1%。微粒体联苯胺/前列腺素氢过氧化活性较低。在胰腺胞质溶胶和微粒体中，4-硝基联苯还原酶活性水平与人肝脏相当。胰腺胞质溶胶的O-乙酰转移酶活性（[3H]N-羟基-ABP的乙酰辅酶A依赖性DNA结合）较高，约为人结肠中测量水平的三分之二。胞质溶胶对对氨基苯甲酸的N-乙酰化活性较高，但对磺胺二甲嘧啶则无此活性，这表明乙酰转移酶-1（NAT1）在该组织中主要表达。胞质溶胶中的磺基转移酶检测水平较低。使用经丁醇萃取增强的32P后标记法，在大多数样品中检测到了推定的芳胺-DNA加合物。此外，在29个DNA样品中的8个中，观察到一种主要加合物，其色谱图与主要的ABP-DNA加合物N-（脱氧鸟苷-8-基）-ABP相同。这些结果与芳香胺和硝基芳烃可能参与人类胰腺癌病因学的假说一致。
