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Cyp1b1 Exerts Opposing Effects on Intestinal Tumorigenesis via Exogenous and Endogenous Substrates

Departments of ¹ Pharmacology and ² Oncology, University of Wisconsin, Madison, Wisconsin

Requests for reprints: Colin R. Jefcoate, Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706. Phone: 608-263-3975; Fax: 608-262-1257; E-mail: jefcoate{at}wisc.edu.

Key Words: Cytochrome P450 1B1 (Cyp1b1, mouse; CYP1B1, human) • Adenomatous polyposis coli (Apc) • Polycyclic aromatic hydrocarbons (PAH) • DMBA • Intestinal neoplasia

Cytochrome P450 1B1 (Cyp1b1) metabolism contributes to physiologic 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 days) Cyp1b1-deficient Min mice selectively 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-IB kinase, and RelA, 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 with 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 the absence of Cyp1b1. Cyp1b1 metabolism of DMBA and endogenous oxygenation products may each affect a tumor-promoting nuclear factor-B activation, whereas Ah receptor activation by PAH affects suppression. Tumorigenesis may, therefore, depend on activation of PAH by Cyp1b1 and on offsetting suppression by Cyp1b1 of endogenous tumor-enhancing substrates. [Cancer Res 2008;68(18):7394–402]