Cyp1b1 exerts opposing effects on intestinal tumorigenesis via exogenous and endogenous substrates.
Cyp1b1 exerts opposing effects on intestinal tumorigenesis via exogenous and endogenous substrates.
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DOI：
10.1158/0008-5472.can-07-6750
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发表时间：
2008-09-15
期刊：
影响因子：
11.2
通讯作者：
Jefcoate CR
中科院分区：
文献类型：
--
作者：
Halberg RB;Larsen MC;Elmergreen TL;Ko AY;Irving AA;Clipson L;Jefcoate CR
Cytochrome P450 1B1 (Cyp1b1) metabolism contributes to physiological functions during embryogenesis, but also to carcinogenic activation of polycyclic aromatic hydrocarbons (PAH). We generated Cyp1b1-deficient mice carrying the Min allele of the Adenomatous polyposis coli gene. These Cyp1b1-deficient Min mice developed twice as many tumors as Min controls, which, however, remained similar in size and histology. Tumors from older (130 day) Cyp1b1-deficient Min mice exhibited focal areas of nuclear atypia associated with less organized epithelia. The metabolism of endogenous substrates by Cyp1b1, therefore, suppresses tumor initiation, but also affects progression. Treatment of Min mice with 7,12-dimethylbenzanthracene (DMBA) doubled both tumor multiplicity and size within 20 days, but not when mice lacked Cyp1b1. This was paralleled by an abnormal staining of crypts with β catenin, phospho-IKK, and ReIA, which may represent an early stage of tumorigenesis similar to aberrant crypt formation. Cyp1b1 deletion did not affect circulating DMBA and metabolites. Cyp1b1 expression was higher in the tumors compared to normal small intestines. Increased tumorigenesis may, therefore, arise from generation of DMBA metabolites by Cyp1b1 in the developing tumors. Benzo(a)pyrene (BP), which is similarly activated by Cyp1b1 in vitro, did not affect tumorigenesis in Min mice. By contrast, BP and DMBA each suppressed tumor multiplicity in absence of Cyp1b1. Cyp1b1 metabolism of DMBA and endogenous oxygenation products may each impact a tumor promoting NF-κB. activation, whereas Ah receptor activation by PAH effects suppression. Tumorigenesis may, therefore, depend on activation of PAH by Cyp1b1, and on off-setting suppression by Cyp1b1 of endogenous tumor-enhancing substrates.
