Studies on the Mechanism of Stimulation of Microsomal H2O2 Formation and Benzo(a)pyrene Hydroxylaton by Substrates and Flavone

Hildebrandt, Alfred G.; Bergs, C.; Heinemeyer, Gerhard; Schlede, Eva; Roots, Ivar; Abbas-Ali, B.; Schmoldt, A.

doi:10.1007/978-1-4757-0674-1_11

Cited by 11 publications

(6 citation statements)

References 24 publications

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“…The formation of H 2 O 2 by microsomal cytochromes P450 has been consistently observed, particularly with uncoupled substrates (19,33) including BP (20). Recently, in vitro experiments studying electron transport during the catalytic cycle of human CYP1A1 showed that this enzyme could produce H 2 O 2 (43).…”

Section: Discussionmentioning

confidence: 98%

An Autoregulatory Loop Controlling CYP1A1 Gene Expression: Role of H₂O₂and NFI

Morel

Mermod

Barouki

1999

Molecular and Cellular Biology

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Cytochrome P450 1A1 (CYP1A1), like many monooxygenases, can produce reactive oxygen species during its catalytic cycle. Apart from the well-characterized xenobiotic-elicited induction, the regulatory mechanisms involved in the control of the steady-state activity of CYP1A1 have not been elucidated. We show here that reactive oxygen species generated from the activity of CYP1A1 limit the levels of induced CYP1A1 mRNAs. The mechanism involves the repression of the CYP1A1 gene promoter activity in a negative-feedback autoregulatory loop. Indeed, increasing the CYP1A1 activity by transfecting CYP1A1 expression vectors into hepatoma cells elicited an oxidative stress and led to the repression of a reporter gene driven by the CYP1A1 gene promoter. This negative autoregulation is abolished by ellipticine (an inhibitor of CYP1A1) and by catalase (which catalyzes H(2)O(2) catabolism), thus implying that H(2)O(2) is an intermediate. Down-regulation is also abolished by the mutation of the proximal nuclear factor I (NFI) site in the promoter. The transactivating domain of NFI/CTF was found to act in synergy with the arylhydrocarbon receptor pathway during the induction of CYP1A1 by 2,3,7,8-tetrachloro-p-dibenzodioxin. Using an NFI/CTF-Gal4 fusion, we show that NFI/CTF transactivating function is decreased by a high activity of CYP1A1. This regulation is also abolished by catalase or ellipticine. Consistently, the transactivating function of NFI/CTF is repressed in cells treated with H(2)O(2), a novel finding indicating that the transactivating domain of a transcription factor can be targeted by oxidative stress. In conclusion, an autoregulatory loop leads to the fine tuning of the CYP1A1 gene expression through the down-regulation of NFI activity by CYP1A1-based H(2)O(2) production. This mechanism allows a limitation of the potentially toxic CYP1A1 activity within the cell.

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Section: Discussionmentioning

confidence: 98%

An Autoregulatory Loop Controlling CYP1A1 Gene Expression: Role of H₂O₂and NFI

Morel

Mermod

Barouki

1999

Molecular and Cellular Biology

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“…It has been proved that the carcinogenicity of B[a]P was highly associated with the oxidative stress (Kim and Lee 1997). The oxidative stress could be generated in the biotransformation reaction of B[a]P by cytochrome P450 (CYP) (Hildebrandt et al 1981;Joseph and Jaiswal 1998).…”

Section: Introductionmentioning

confidence: 99%

β-carotene and retinol reduce benzo[a]pyrene-induced mutagenicity and oxidative stress via transcriptional modulation of xenobiotic metabolizing enzymes in human HepG2 cell line

Darwish

Ikenaka

Nakayama

et al. 2017

Environ Sci Pollut Res

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Benzo[a]pyrene (B[a]P) is one of the polycyclic aromatic hydrocarbons which is formed due to smoking of foods, incomplete combustion of woods, vehicle exhausts, and cigarettes smokes. B[a]P gets entry into human and animal bodies mainly through their diets. Metabolic activation of B[a]P is required to induce mutagenesis and carcinogenesis in animal and human studies. Carotenoids and retinoids are phytochemicals that if ingested have multiple physiological interferences in the human and animal bodies. In this study, we firstly investigated the protective effects of β-carotene, β-apo-8-carotenal, retinol, and retinoic acid against B[a]P-induced mutagenicity and oxidative stress in human HepG2 cells. Secondly, we tested the hypothesis of modulating xenobiotic metabolizing enzymes (XMEs) by carotenoids and retinoids as a possible mechanism of protection by these micronutrients against B[a]P adverse effects. The obtained results declared that β-carotene and retinol significantly reduced B[a]P-induced mutagenicity and oxidative stress. Tested carotenoids and retinoids reduced B[a]P-induced phase I XMEs and induced B[a]P reduced phase II and III XMEs. Thus, the protective effects of these micronutrients are probably due to their ability of induction of phase II and III enzymes and interference with the induction of phase I enzymes by the promutagen, B[a]P. It is highly recommended to consume foods rich in these micronutrients in the areas of high PAH pollution.

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“…It has been proved that the carcinogenicity of BaP was highly associated with the oxidative stress (Kim and Lee,1997). The oxidative stress could be generated in the process of BaP's biotransformation by cytochrome P450 (Hildebrandt et al,1981; Joseph and Jaiswal,1998).…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress and cell‐cycle change induced by coexposed PCB126 and benzo(a) pyrene to human hepatoma (HepG2) cells

Wei

et al. 2010

Environmental Toxicology

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Benzo(a)pyrene (BaP) never exists in the environment as a single compound but always coexists with other chemicals. These chemicals may affect the toxicity of BaP. Our previous study confirmed that polychlorinated biphenyls (PCBs), which were recently found coexisting with BaP in various environmental media, dramatically enhanced the genotoxicity of BaP. But the known mechanisms associated with this phenomenon are limited. Because BaP's genotoxicity is highly associated with its ability to induce the oxidative stress, we propose that the coexistence of PCBs may enhance BaP's genotoxicity by affecting BaP-induced oxidative stress. In this study, the HepG2 cells were treated with either BaP (50 μM), 3,3',4,4',5-pentachlorobiphenyl (PCB126) (0.01, 0.1, 1, and 10 nM), or pretreated with PCB126 followed by a coexposure to BaP and PCB126. We found that the exposure to BaP alone effectively increased the level of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and the percentage of cells in G0/G1 phase, but decreased the percentage of S-phase cells. Compared to BaP alone, coexposure to both BaP and PCB126 effectively enhanced the levels of ROS and MDA as well as the percentage of cells in S phase, but decreased the levels of GSH and percentage of cells in G0/G1 phase. Our findings suggest that increasing oxidative stress and impairing the normal cell-cycle control may be mechanisms by which PCB126 enhances the genotoxity of BaP exposure.

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Studies on the Mechanism of Stimulation of Microsomal H2O2 Formation and Benzo(a)pyrene Hydroxylaton by Substrates and Flavone

Cited by 11 publications

References 24 publications

An Autoregulatory Loop Controlling CYP1A1 Gene Expression: Role of H₂O₂and NFI

An Autoregulatory Loop Controlling CYP1A1 Gene Expression: Role of H₂O₂and NFI

β-carotene and retinol reduce benzo[a]pyrene-induced mutagenicity and oxidative stress via transcriptional modulation of xenobiotic metabolizing enzymes in human HepG2 cell line

Oxidative stress and cell‐cycle change induced by coexposed PCB126 and benzo(a) pyrene to human hepatoma (HepG2) cells

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Studies on the Mechanism of Stimulation of Microsomal H2O2 Formation and Benzo(a)pyrene Hydroxylaton by Substrates and Flavone

Cited by 11 publications

References 24 publications

An Autoregulatory Loop Controlling CYP1A1 Gene Expression: Role of H2O2and NFI

An Autoregulatory Loop Controlling CYP1A1 Gene Expression: Role of H2O2and NFI

β-carotene and retinol reduce benzo[a]pyrene-induced mutagenicity and oxidative stress via transcriptional modulation of xenobiotic metabolizing enzymes in human HepG2 cell line

Oxidative stress and cell‐cycle change induced by coexposed PCB126 and benzo(a) pyrene to human hepatoma (HepG2) cells

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An Autoregulatory Loop Controlling CYP1A1 Gene Expression: Role of H₂O₂and NFI

An Autoregulatory Loop Controlling CYP1A1 Gene Expression: Role of H₂O₂and NFI