Uno Shigeyuki, Dragin Nadine, Miller Marian L, Dalton Timothy P, Gonzalez Frank J, Nebert Daniel W
Department of Environmental Health, and The Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Free Radic Biol Med. 2008 Feb 15;44(4):570-83. doi: 10.1016/j.freeradbiomed.2007.10.044. Epub 2007 Nov 12.
The CYP1A1, CYP1A2, and CYP1B1 enzymes are inducible by benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); metabolism of BaP by these enzymes leads to electrophilic intermediates and genotoxicity. Throughout the gastrointestinal (GI) tract, we systematically compared basal and inducible levels of the CYP1 mRNAs by Q-PCR, and localized the CYP1 proteins by immunohistochemistry. Cyp1(+/+) wild-type were compared with the Cyp1a1(-/-), Cyp1a2(-/-), and Cyp1b1(-/-) single-knockout and Cyp1a1/1b1(-/-) and Cyp1a2/1b1(-/-) double-knockout mice. Oral BaP was compared with intraperitoneal TCDD. In general, maximal CYP1A1 mRNA levels were 3-10 times greater than CYP1B1, which were 3-10 times greater than CYP1A2 mRNA levels. Highest inducible concentrations of CYP1A1 and CYP1A2 occurred in proximal small intestine, whereas the highest basal and inducible levels of CYP1B1 mRNA occurred in esophagus, forestomach, and glandular stomach. Ablation of either Cyp1a2 or Cyp1b1 gene resulted in a compensatory increase in CYP1A1 mRNA - but only in small intestine. Also in small intestine, although BaP- and TCDD-mediated CYP1A1 inductions were roughly equivalent, oral BaP-mediated CYP1A2 mRNA induction was approximately 40-fold greater than TCDD-mediated CYP1A2 induction. CYP1B1 induction by TCDD in Cyp1(+/+) and Cyp1a2(-/-) mice was 4-5 times higher than that by BaP; however, in Cyp1a1(-/-) animals CYP1B1 induction by TCDD or BaP was approximately equivalent. CYP1A1 and CYP1A2 proteins were generally localized nearer to the lumen than CYP1B1 proteins, in both squamous and glandular epithelial cells. These GI tract data suggest that the inducible CYP1A1 enzyme, both in concentration and in location, might act as a "shield" in detoxifying oral BaP and, hence, protecting the animal.
细胞色素P450 1A1（CYP1A1）、细胞色素P450 1A2（CYP1A2）和细胞色素P450 1B1（CYP1B1）酶可被苯并[a]芘（BaP）和2,3,7,8-四氯二苯并对二恶英（TCDD）诱导；这些酶对BaP的代谢会产生亲电中间体并具有遗传毒性。在整个胃肠道（GI）中，我们通过定量聚合酶链反应（Q-PCR）系统地比较了CYP1 mRNA的基础水平和诱导水平，并通过免疫组织化学对CYP1蛋白进行定位。将Cyp1（+/+）野生型小鼠与Cyp1a1（-/-）、Cyp1a2（-/-）和Cyp1b1（-/-）单敲除小鼠以及Cyp1a1/1b1（-/-）和Cyp1a2/1b1（-/-）双敲除小鼠进行比较。将口服BaP与腹腔注射TCDD进行比较。一般来说，CYP1A1 mRNA的最大水平比CYP1B1高3至10倍，而CYP1B1比CYP1A2 mRNA水平高3至10倍。CYP1A1和CYP1A2的最高诱导浓度出现在近端小肠，而CYP1B1 mRNA的最高基础水平和诱导水平出现在食管、前胃和腺胃。Cyp1a2或Cyp1b1基因的缺失导致CYP1A1 mRNA代偿性增加——但仅在小肠中。同样在小肠中，虽然BaP和TCDD介导的CYP1A1诱导大致相当，但口服BaP介导的CYP1A2 mRNA诱导比TCDD介导的CYP1A2诱导大约高40倍。在Cyp1（+/+）和Cyp1a2（-/-）小鼠中，TCDD对CYP1B1的诱导比BaP高4至5倍；然而，在Cyp1a1（-/-）动物中，TCDD或BaP对CYP1B1的诱导大致相当。在鳞状上皮细胞和腺上皮细胞中，CYP1A1和CYP1A2蛋白通常比CYP1B1蛋白更靠近管腔定位。这些胃肠道数据表明，可诱导的CYP1A1酶在浓度和位置上都可能作为一种“屏障”来解毒口服的BaP，从而保护动物。
