Fetal MouseCyp1b1and Transplacental Carcinogenesis from Maternal Exposure to Dibenzo(a,l)pyrene

Abstract

Dibenzo(a,l)pyrene (DBP) is among the most potent carcinogenic polycyclic aromatic hydrocarbons. Previously, we showed that DBP administration to pregnant mice resulted in high mortality of offspring from an aggressive T-cell lymphoma. All mice that survive to 10 months of age exhibit lung tumors with high multiplicity. Recombinant cytochrome P450 (cyp) 1b1 from mice and the homologue 1B1 in humans exhibit high activity toward the metabolic activation of DBP. Targeted disruption of the cyp1b1 gene protects against most DBP-dependent cancers. Mice heterozygous for the disrupted cyp1b1 allele were used to examine the effect of cyp1b1 gene dosage on DBP transplacental carcinogenesis. Dams were treated with 1 or 15 mg/kg of DBP or 50 mg/kg of benzo(a)pyrene. Cyp1b1-null offspring did not develop lymphoma, whereas wild-type and heterozygous siblings, born to dams given the high dose of DBP, exhibited significant mortalities between 10 and 30 weeks of age. At 10 months, all groups had lung adenomas or carcinomas [9.5%, 40.3%, 25.6%, and 100% incidences for controls, benzo(a)pyrene, 1 and 15 mg/kg DBP, respectively]. Cyp1b1 status did not alter benzo(a)pyrene-dependent carcinogenesis. At 1 mg/kg DBP, cyp1b1 status altered the incidence of lung tumors (19.0, 27.8, and 28.6% for nulls, heterozygous, and wild-type, respectively). At 15 mg/kg, tumor multiplicities in cyp1b1 wild-type (9.3) and heterozygous (9.5) offspring were nearly twice that of cyp1b1-null siblings (5.0). These data confirm that cyp1b1 bioactivation of DBP occurs in fetal target tissues, following transplacental exposure, with the thymus and lung as primary and secondary targets, respectively.

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

“…The activation of MMPs is associated with increased oxidative stress. 18,38 We have previously reported that Ang II generates ROSs from arachidonic acid via CYP1B1. 11 CYP1B1 can metabolize various substrates, including steroids, retinoic acid, and fatty acids.…”

“…Animals were routinely genotyped using the following primers: ApoE forward-1, 5 0 -GCCTAGCCGAGGGAGAGCCG-3 0 ; ApoE forward-2, 5 0 -TGTGACTTGGGAGCTCTGCAGC-3 0 ; ApoE reverse, 5 0 -GCCGCCCCGACTGCATCT-3 0 , as described 17 ; CYP1B1-3 forward, 5 0 -TTTGCCTGTCACC-ATTCCAC-3 0 ; CYP1B1-3 reverse, 5 0 -ACGACTTGGGCT-TAATGGTC-3 0 ; NEO-1, 5 0 -TGAATGAACTGCAGGA-CGAG-3 0 ; and NEO-2, 5 0 -CCACAGTCGATGAATCCA-GA-3 0 , as described. 18 Their genotypes were confirmed by PCR analysis. Male Apoe À/À /Cyp1b1 þ/þ and Apoe À/À / Cyp1b1 À/À mice, approximately 16 weeks of age and weighing 28 to 32 g, were used in all experiments.…”

Targeting Drug-Metabolizing Enzymes for Effective Chemoprevention and Chemotherapy

“…5). Whereas green tea was found to protect against DBP-induced lymphoma mortality, this protective effect seemed to be primarily due to the caffeine but not to the EGCG components of the tea (Castro et al, 2008). However, with respect to DBP-induced lung adenomas, all treatments (i.e., caffeinated and decaffeinated green tea, caffeine, and EGCG) were found to decrease tumor multiplicity.…”

“…One of the best examples of therapeutic success obtained using a P450-inhibition strategy to target P450s with cancer-modifying properties is illustrated by the CYP19 (aromatase) inhibitor/breast cancer paradigm and, as described herein, a CYP17 inhibitor/prostate cancer paradigm (Bruno and Njar, 2007). Second, observations were made on P450s, such as CYP1B1, suggesting that they are up-regulated in a number human cancers and that modifications in the expression levels of at least CYP1B1 can significantly modulate tumor progression (Castro et al, 2008). These findings indicate that approaches designed to inhibit CYP1B1 expression may provide a chemopreventive/therapeutic benefit.…”

The Inhibitory Effect of Natural Stilbenes and Their Analogues on Catalytic Activity of Cytochromes P450 Family 1 in Comparison with Other Phenols - Structure and Activity Relationship

“…In humans, CYP1B1 is overexpressed in tumor cells, and this has important implications for tumor development and progression (Castro et al, 2008). It was found that CYP1B1 knockout mice were highly resistant to 7,12-dimethylbenz[a]anthracene induced tumor formation (Gonzalez, 2002).…”