atypical cytochrome P450 induction profiles in glomerular mesangial cells at the mRNA and enzyme level

Bowes, Russell C.; Parrish, Alan R.; Steinberg, Michael A.; Willett, Kristine L.; Zhao, Wei; Savas, Üzen; Jefcoate, Colin R.; Safe, Stephen; Ramos, Kenneth S.

doi:10.1016/0006-2952(96)00310-3

Cited by 35 publications

(13 citation statements)

References 26 publications

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“…3), demonstrates a pivotal role for CYP1B1 in the metabolic activation of BP, 3-OH-BP, and BPQ to genotoxic metabolites. These results support earlier findings that CYP1B1 contributes to PAH activation (Bowes et al, 1996; Shimada et al, 1996; Kerzee and Ramos, 2001). The fact that the major BP adduct 2, adduct 1 of 3-OH-BP, and adduct 2 of BPQ were identical (Fig.…”

Section: Discussionsupporting

confidence: 91%

“…1) showing concentration-dependent formation (Tables 1-3) of multiple DNA adducts in SMCs exposed to BP and its metabolites indicates that BP, 3-OH-BP, and BPQ are potent genotoxic agents in these cells. In fact, these studies indicate the presence in the SMCs of an enzymatic system that activates PAHs (Bowes et al, 1996;Shimada et al, 1996;Moorthy et al, 2002). The rationale for choosing the concentration range (0.03 to 3 M) of BP was based on previous studies (Lu and Ramos, 1998) showing that treatment of mouse vascular SMCs with 3 M BP results in activation of L1Md retrotransposon, which when coupled to DNA damage and inhibition of DNA repair, may be linked to the atherogenic response of BP.…”

Section: Discussionmentioning

confidence: 99%

“…CYP1A1 and 1B1 activities are frequently determined by measuring the activities of aryl hydrocarbon hydroxylase (AHH), which catalyzes the conversion of BP to 3-hydroxybenzo[a]pyrene (3-OH-BP) (Nebert and Gelboin, 1968). PAHs are potent inducers of CYP1B1 (Shimada et al, 1996), and metabolic activation of PAHs by CYP1B1 to oxidative intermediates and carcinogenic precursors (Bowes et al, 1996;Shimada et al, 1996;Moorthy et al, 2002) may have implications for PAH-induced atherogenesis. Taken together, it appears that CYP1B1-catalyzed BP metabolism to oxidative intermediates plays an important role in BP genotoxicity, which may in turn contribute to atherogenesis.…”

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confidence: 99%

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Role of Cytochrome P4501B1 in Benzo[a]pyrene Bioactivation to DNA-Binding Metabolites in Mouse Vascular Smooth Muscle Cells: Evidence from³²P-Postlabeling for Formation of 3-Hydroxybenzo[a]pyrene and Benzo[a]pyrene-3,6-quinone as Major Proximate Genotoxic Intermediates

Moorthy¹,

Miller²,

Jiang³

et al. 2003

J Pharmacol Exp Ther

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Benzo [a]pyrene (BP), a polycylic aromatic hydrocarbon (PAH), is a potent atherogen and carcinogen in laboratory animals. Since genotoxic mechanisms may contribute to the development of atherosclerosis by PAHs, we have tested the hypotheses that: 1) BP induces DNA adducts in mouse aortic smooth muscle cells (SMCs); 2) 3-hydroxybenzo[a]pyrene (3-OH-BP) and benzo [a]pyrene-3,6-quinone (BPQ) are proximate genotoxic metabolites; and 3) cytochrome P4501B1 (CYP1B1) mediates the activation of BP and its metabolites to ultimate genotoxic intermediates. Cultured mouse aortic SMCs were treated with BP, 3-OH-BP, or BPQ for 24 h, and DNA adduct formation was analyzed by 32 P-postlabeling. In some experiments, cells were pretreated with the CYP1B1 inhibitor 1-ethynylpyrene (EP) prior to exposure to BP or its metabolites. BP, 3-OH-BP, and BPQ induced formation of several DNA adducts that were not observed in dimethylsulfoxide-treated cells. Reand cochromatography experiments indicated that 3-OH-BP and BPQ were proximate genotoxic metabolites of BP. DNA adduct formation was strongly inhibited by EP, a specific inhibitor of CYP1B1. BP treatment of SMCs resulted in induction of aryl hydrocarbon hydroxylase (AHH) activity and CYP1B1, but not CYP1A1, apoprotein. EP also blocked AHH induction by BP. In conclusion, the results of this study support the hypothesis that in SMCs, which are target sites for the development of atherosclerosis, the major bioactivation pathway of BP entails CYP1B1-mediated formation of the 3-OH-BP and BPQ, which are proximate genotoxic metabolites that may in turn get transformed to ultimate DNA-binding metabolites, which may contribute to atherogenesis by PAHs.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Role of Cytochrome P4501B1 in Benzo[a]pyrene Bioactivation to DNA-Binding Metabolites in Mouse Vascular Smooth Muscle Cells: Evidence from³²P-Postlabeling for Formation of 3-Hydroxybenzo[a]pyrene and Benzo[a]pyrene-3,6-quinone as Major Proximate Genotoxic Intermediates

Moorthy¹,

Miller²,

Jiang³

et al. 2003

J Pharmacol Exp Ther

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“…Despite the structural similarity between CYP1A1 and CYP 1 A2, substrate specificity has been observed. Benzo(a)pyrene (BaP) is specifically metabolized by CYP1A1, whereas acetanilide is metabolized by CYP1A2 (6,33). An aryl hydrocarbon receptor (AhR)-null mouse was produced and completely lacks the expression of CYP1A1 and exhibits low expression of CYP 1 A2 and uridine diphosphate-glucuronosyltranferase (17).…”

Section: Ethanolmentioning

confidence: 99%

Using Cytochrome P-450 Gene Knock-Out Mice to Study Chemical Metabolism, Toxicity, and Carcinogenicity

2000

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Cytochrome P-450 (CYP) enzymes are heme-containing proteins that carry out oxidative metabolism of a wide range of structurally diverse exogenous chemicals and therapeutic agents as well as endogenous compounds. For some of these xenobiotics, oxidative metabolism results in the formation of toxic, mutagenic, or carcinogenic metabolites. In the past, the role of CYP enzymes in metabolism and chemical-induced toxicity was studied indirectly through use of specific antibodies or inducers and inhibitors of these enzymes. Progress in molecular biology and the ability to bioengineer animal models that do not express CYP1A2, CYP1A1, CYP1B1, CYP2E1, or both CYP1A2 and CYP2E1 isozymes has allowed for direct investigations of the in vivo role of these enzymes in the metabolism, toxicity, and carcinogenicity of xenobiotics. This article reviews research conducted to date that utilizes these genetically bioengineered mice in metabolism, toxicity, or carcinogenicity studies of chemicals. Some studies showed a positive correlation between in vivo results and in vitro predictions for the role of a specific CYP in chemical-induced effects, whereas other studies did not support in vitro predictions. Work reviewed herein demonstrates the importance of using animal models for investigating the role of specific CYP enzymes in metabolism and chemical-induced toxicity or carcinogenicity rather than relying solely on in vitro techniques. Eventually, studies of this nature will facilitate a more accurate assessment of human risks with regard to chemicals by helping us to understand the relationships between chemical metabolism, carcinogenicity, and polymorphisms in CYP enzymes.

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“…The CYP1A family comprises two proteins CYP1A1 and 1A2, which play important roles in carcinogen activation (Guengerich, 1988). Recent studies have shown CYP1B1 also to be active in PAH-mediated carcinogenesis (Bowes et al, 1996;Shimada et al, 1996). The hepatic CYP1A1/1A2 enzymes are inducible by a number of chemicals, including the hepatocarcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Whitlock, 1987), MC (Thomas et al, 1983), benzo [a]pyrene (Conney, 1986), and cigarette smoke (Kawajiri et al, 1990).…”

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confidence: 99%

Differential Regulation of Expression of Hepatic and Pulmonary Cytochrome P4501A Enzymes by 3-Methylcholanthrene in Mice Lacking theCYP1A2Gene

Kondraganti

Jiang

Moorthy

2002

J Pharmacol Exp Ther

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The cytochrome P4501A enzymes play important roles in carcinogen metabolism. We reported previously that 3-methylcholanthrene (MC) elicits a persistent induction of hepatic, pulmonary, and mammary microsomal cytochrome P450 (P450) 1A enzymes for several weeks after MC withdrawal. In this study, we tested the hypothesis that CYP1A2, a liver-specific P450 isozyme, plays an important role in the mechanisms governing persistent CYP1A1 induction by MC in liver but not in extra-hepatic tissues such as lung, which is devoid of endogenous CYP1A2. Administration of wild-type (WT) or CYP1A2-null mice with MC (100 mol/kg i.p.) once daily for 4 days caused significant increases in hepatic CYP1A1/1A2 activities, apoprotein contents, and mRNA levels 1 day after carcinogen withdrawal compared with vehicle-treated controls. The induction persisted in the WT, but not CYP1A2-null animals, for up to 15 days. In the lung, MC caused persistent CYP1A1 induction for 15 days in both the genotypes. Since MC is almost completely eliminated by day 15, we hypothesize that CYP1A2 contributes to the up-regulation of CYP1A1 in liver, but not lung, by a novel mechanism, presumably involving a CYP1A2-dependent persistent metabolite. The studies demonstrate tissue-specific differences in the regulation of CYP1A by MC, a phenomenon that may have implications for human carcinogenesis caused by environmental chemicals.

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atypical cytochrome P450 induction profiles in glomerular mesangial cells at the mRNA and enzyme level

Cited by 35 publications

References 26 publications

Role of Cytochrome P4501B1 in Benzo[a]pyrene Bioactivation to DNA-Binding Metabolites in Mouse Vascular Smooth Muscle Cells: Evidence from³²P-Postlabeling for Formation of 3-Hydroxybenzo[a]pyrene and Benzo[a]pyrene-3,6-quinone as Major Proximate Genotoxic Intermediates

Role of Cytochrome P4501B1 in Benzo[a]pyrene Bioactivation to DNA-Binding Metabolites in Mouse Vascular Smooth Muscle Cells: Evidence from³²P-Postlabeling for Formation of 3-Hydroxybenzo[a]pyrene and Benzo[a]pyrene-3,6-quinone as Major Proximate Genotoxic Intermediates

Using Cytochrome P-450 Gene Knock-Out Mice to Study Chemical Metabolism, Toxicity, and Carcinogenicity

Differential Regulation of Expression of Hepatic and Pulmonary Cytochrome P4501A Enzymes by 3-Methylcholanthrene in Mice Lacking theCYP1A2Gene

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atypical cytochrome P450 induction profiles in glomerular mesangial cells at the mRNA and enzyme level

Cited by 35 publications

References 26 publications

Role of Cytochrome P4501B1 in Benzo[a]pyrene Bioactivation to DNA-Binding Metabolites in Mouse Vascular Smooth Muscle Cells: Evidence from32P-Postlabeling for Formation of 3-Hydroxybenzo[a]pyrene and Benzo[a]pyrene-3,6-quinone as Major Proximate Genotoxic Intermediates

Role of Cytochrome P4501B1 in Benzo[a]pyrene Bioactivation to DNA-Binding Metabolites in Mouse Vascular Smooth Muscle Cells: Evidence from32P-Postlabeling for Formation of 3-Hydroxybenzo[a]pyrene and Benzo[a]pyrene-3,6-quinone as Major Proximate Genotoxic Intermediates

Using Cytochrome P-450 Gene Knock-Out Mice to Study Chemical Metabolism, Toxicity, and Carcinogenicity

Differential Regulation of Expression of Hepatic and Pulmonary Cytochrome P4501A Enzymes by 3-Methylcholanthrene in Mice Lacking theCYP1A2Gene

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Role of Cytochrome P4501B1 in Benzo[a]pyrene Bioactivation to DNA-Binding Metabolites in Mouse Vascular Smooth Muscle Cells: Evidence from³²P-Postlabeling for Formation of 3-Hydroxybenzo[a]pyrene and Benzo[a]pyrene-3,6-quinone as Major Proximate Genotoxic Intermediates

Role of Cytochrome P4501B1 in Benzo[a]pyrene Bioactivation to DNA-Binding Metabolites in Mouse Vascular Smooth Muscle Cells: Evidence from³²P-Postlabeling for Formation of 3-Hydroxybenzo[a]pyrene and Benzo[a]pyrene-3,6-quinone as Major Proximate Genotoxic Intermediates