Role of Cytochrome P4501 Family Members in the Metabolic Activation of Polycyclic Aromatic Hydrocarbons in Mouse Epidermis

Kleiner, Heather E.; Vulimiri, Suryanarayana V.; Hatten, William B.; Reed, Melissa J.; Nebert, Daniel W.; Jefcoate, Colin R.; DiGiovanni, John

doi:10.1021/tx049919c

Cited by 75 publications

(52 citation statements)

References 35 publications

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“…In this same study, the cancer incidence at most sites markedly declined in Cyp1b1 knockout mice of the same genetic background. These results are consistent with other studies showing Cyp1b1 to be the most efficient cytochrome P450 enzyme in bioactivation of DBP (15)(16)(17)(18)29) and to be required for DBP-or 7,12-dimethylbenz(a)annthracene-induced carcinogenesis (29,(34)(35)(36)50).…”

Section: Discussionsupporting

confidence: 93%

“…In contrast, if the fetus is AHR responsive, the tumor incidence is higher regardless of the maternal phenotype (10)(11)(12)(13). AHR regulates Cyp1a1 and/or Cyp1b1, both of which metabolize 3-methylcholanthrene (and other PAHs) to carcinogenic metabolites (11,12,(14)(15)(16)(17)(18). In the AHR-responsive mother, induction of Cyp1a1 and/or Cyp1b1 is thought to result in enhanced maternal metabolism and reduced bioavailability to the fetus compared with the nonresponsive mother (19,20).…”

Section: Introductionmentioning

confidence: 99%

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In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

Loehr²,

Fischer³

et al. 2006

Cancer Research

102

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Lymphoma and leukemia are the most common cancers in children and young adults; in utero carcinogen exposure may contribute to the etiology of these cancers. A polycyclic aromatic hydrocarbon (PAH), dibenzo [a,l]pyrene (DBP), was given to pregnant mice (15 mg/kg body weight, gavage) on gestation day 17. Significant mortalities in offspring, beginning at 12 weeks of age, were observed due to an aggressive T-cell lymphoblastic lymphoma. Lymphocytes invaded numerous tissues. All mice surviving 10 months, exposed in utero to DBP, exhibited lung tumors; some mice also had liver tumors. To assess the role of the aryl hydrocarbon receptor (AHR) in DBP transplacental cancer, B6129SF1/J (AHR b-1/d , responsive) mice were crossed with strain 129S1/SvIm (AHR d/d , nonresponsive) to determine the effect of maternal and fetal AHR status on carcinogenesis. Offspring born to nonresponsive mothers had greater susceptibility to lymphoma, irrespective of offspring phenotype. However, when the mother was responsive, an AHR-responsive phenotype in offspring increased mortality by 2-fold. In DBP-induced lymphomas, no evidence was found for TP53, B-catenin, or Ki-ras mutations but lung adenomas of mice surviving to 10 months of age had mutations in Ki-ras codons 12 and 13. Lung adenomas exhibited a 50% decrease and a 35-fold increase in expression of Rb and p19/ARF mRNA, respectively. This is the first demonstration that transplacental exposure to an environmental PAH can induce a highly aggressive lymphoma in mice and raises the possibility that PAH exposures to pregnant women could contribute to similar cancers in children and young adults. (Cancer Res 2006; 66(2): 755-62)

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

Loehr²,

Fischer³

et al. 2006

Cancer Research

102

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“…The benzo(a)pyrene group was included as a negative control. Benzo(a)pyrene, like DBP, is a potent carcinogenic PAH, but is bioactivated primarily by cyp1a1 and cyp1a2 rather than by cyp1b1 (12,19,20). For this reason, we expected to see few, if any, lymphomas and no significant difference between siblings of different cyp1b1 genotypes with respect to benzo(a)pyrene-dependent transplacental carcinogenesis.…”

Section: Resultsmentioning

confidence: 95%

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

Castro

Baird

Pereira

et al. 2008

Cancer Prevention Research

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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.

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“…The 3,4-diol metabolite undergoes epoxidation by CYP 1A1 and CYP 1B1 to form the ultimate ovotoxicant and carcinogen, DMBA-3,4-diol-1,2-epoxide. 58,59 CYP 1A1, CYP 1B1 and mEH enzymes (mRNA and protein) are expressed in the mouse ovary and the mRNA for these enzymes are induced by DMBA in both dose-and timedependent manners. 52,53,60,61 Early studies determined that DMBA needed to be bioactivated in order for induction of ovotoxicity.…”

Section: 12-dimethylbenz[a]anthracenementioning

confidence: 99%

Ovarian Metabolism of Xenobiotics

Keating¹

2013

Target Organ Toxicology Series

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At birth, the mammalian ovary contains a finite number of primordial follicles, which once depleted, cannot be replaced. Xenobiotic exposures can destroy primordial follicles resulting in premature ovarian failure and, consequently, early entry into menopause. A number of chemical classes can induce premature ovarian failure, including environmental, chemotherapeutic and industrial exposures. While our knowledge on the mechanistic events that occur in the ovary with chemical exposures is increasing, our understanding of the ovary's capacity to metabolize such compounds is less established. This review will focus on three chemicals for which information on ovarian metabolism is known: trichloroethylene, 7,12-dimethylbenz[a]anthracene and 4-vinylcyclohexene. The current state of understanding of ovarian bioactivation and detoxification processes for each will be described.

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Role of Cytochrome P4501 Family Members in the Metabolic Activation of Polycyclic Aromatic Hydrocarbons in Mouse Epidermis

Cited by 75 publications

References 35 publications

In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

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

Ovarian Metabolism of Xenobiotics

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