Organochlorine insecticides: impacts on human HepG2 cytochrome P4501A, 2B activities and glutathione levels

Dehn, Paula F.; Allen-Mocherie, S.; Karek, J.; Thenappan, A.

doi:10.1016/j.tiv.2004.10.002

Cited by 46 publications

(24 citation statements)

References 73 publications

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“…Moreover, the GSH level in primary cultures of rat hepatocytes is reported to be 40 -60 nmol/10 6 cells [74,75], which is equivalent to a concentration of 8 -12 mM (calculated assuming the volume of a single hepatocyte cell equal to 4940 µm 3 [76]). This concentration is subject to substantial changes in response to various stimuli [41,48,73,77,78]. In particular, exposure of human hepatocarcinoma Hep2 cells to organochlorine insecticides, such as DDT, decreases the GSH concentration from 4 -5 down to 1.2 -1.5 mM (calculated from [48] assuming the protein content in hepatocytes to be of 220 mg/g [79]).…”

Section: Discussionmentioning

confidence: 99%

“…This concentration is subject to substantial changes in response to various stimuli [41,48,73,77,78]. In particular, exposure of human hepatocarcinoma Hep2 cells to organochlorine insecticides, such as DDT, decreases the GSH concentration from 4 -5 down to 1.2 -1.5 mM (calculated from [48] assuming the protein content in hepatocytes to be of 220 mg/g [79]). Therefore, the estimate of 0.5 -1.3 mM for the concentration of GSH exhibiting a half-maximal effect on the Hill coefficient for O-debenzylation of BFC and BQ is certainly consistent with the physiological relevance of this newly-discovered regulatory interaction.…”

Section: Discussionmentioning

confidence: 99%

“…Quite the opposite, it has been suggested that the activation of CYP3A4 by GSH may cause a disruption of regulation of cellular GSH level due to increased production of reactive oxygen species by P450 [48]. Furthermore, the effect of GSH on CYP3A4 observed in reconstituted systems has never been reproduced in microsomes.…”

Section: Introductionmentioning

confidence: 99%

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Effect of glutathione on homo- and heterotropic cooperativity in cytochrome P450 3A4

Davydov

Davydova

Tsalkova

et al. 2008

Archives of Biochemistry and Biophysics

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Glutathione (GSH) exerted a profound effect on the oxidation of 7-benzyloxy-4-(trifluoromethyl) coumarin (BFC) and 7-benzyloxyquinoline (BQ) by human liver microsomes as well as by CYP3A4-containing insect cell microsomes (Baculosomes). The cooperativity in O-debenzylation of both substrates is eliminated in the presence of 1-4 mM GSH. Addition of GSH also increased the amplitude of the 1-PB induced spin shift with purified CYP3A4 and abolished the cooperativity of 1-PB or BFC binding. Changes in fluorescence of 6-bromoacetyl-2-dimethylaminonaphthalene attached to the cysteine-depleted mutant CYP3A4(C58,C64) suggest a GSH-induced conformational changes in proximity of α-helix A. Importantly, the K S value for formation of the GSH complex and the concentrations in which GSH decreases CYP3A4 cooperativity are consistent with the physiological concentrations of GSH in hepatocytes. Therefore, the allosteric effect of GSH on CYP3A4 may play an important role in regulation of microsomal monooxygenase activity in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of glutathione on homo- and heterotropic cooperativity in cytochrome P450 3A4

Davydov

Davydova

Tsalkova

et al. 2008

Archives of Biochemistry and Biophysics

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“…However, mechanisms of action of endosulfan and methoxychlor in humans remain poorly understood. Studies using primary human hepatocytes have shown that endosulfan caused an oxidative stress and that both endosulfan and methoxychlor enhanced transcription of CYP3A4 and CYP2B6 genes, but effects on their corresponding enzyme activities remained unclear (Dehn et al, 2005;Casabar et al, 2010;Kublbeck et al, 2011;Rouimi et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Interactions of Endosulfan and Methoxychlor Involving CYP3A4 and CYP2B6 in Human HepaRG Cells

et al. 2014

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Humans are usually exposed to several pesticides simultaneously; consequently, combined actions between pesticides themselves or between pesticides and other chemicals need to be addressed in the risk assessment. Many pesticides are efficient activators of pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR), two major nuclear receptors that are also activated by other substrates. In the present work, we searched for interactions between endosulfan and methoxychlor, two organochlorine pesticides whose major routes of metabolism involve CAR-and PXR-regulated CYP3A4 and CYP2B6, and whose mechanisms of action in humans remain poorly understood. For this purpose, HepaRG cells were treated with both pesticides separately or in mixture for 24 hours or 2 weeks at concentrations relevant to human exposure levels. In combination they exerted synergistic cytotoxic effects. Whatever the duration of treatment, both compounds increased CYP3A4 and CYP2B6 mRNA levels while differently affecting their corresponding activities. Endosulfan exerted a direct reversible inhibition of CYP3A4 activity that was confirmed in human liver microsomes. By contrast, methoxychlor induced this activity. The effects of the mixture on CYP3A4 activity were equal to the sum of those of each individual compound, suggesting an additive effect of each pesticide. Despite CYP2B6 activity being unchanged and increased with endosulfan and methoxychlor, respectively, no change was observed with their mixture, supporting an antagonistic effect. Altogether, our data suggest that CAR and PXR activators endosulfan and methoxychlor can interact together and with other exogenous substrates in human hepatocytes. Their effects on CYP3A4 and CYP2B6 activities could have important consequences if extrapolated to the in vivo situation.

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“…Interspecies differences in the mixed function oxidase (MFO) induction as biomarker of exposure to different environmental contaminants: the evaluation in fibroblast cell cultures with immunofluorescence technique of the presence and the induction of two components (CYP1A1 and CYP2B) of the cytochrome P450 monooxygenase system (MFO), among the most relevant in drug and xenobiotic metabolism, was used to evaluate interspecies sensitivities to various classes of environmental contaminants. In particular CYP1A1 is induced by planar compounds such as planar OCs (coplanar polychlorinated biphenyls (PCBs)) and PAHs [16] and CYP2B by globular compounds such as PBDEs, PCBs and OC insecticides such as dichlorodiphenyltrichloroethane (DDT) and its metabolites [17,18].…”

Section: Introductionmentioning

confidence: 99%

“Test Tube Cetaceans”: From the Evaluation of Susceptibility to the Study of Genotoxic Effects of Different Environmental Contaminants Using Cetacean Fibroblast Cell Cultures

Marsili¹,

Maltese²,

Coppola³

et al. 2012

New Approaches to the Study of Marine Mammals

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Organochlorine insecticides: impacts on human HepG2 cytochrome P4501A, 2B activities and glutathione levels

Cited by 46 publications

References 73 publications

Effect of glutathione on homo- and heterotropic cooperativity in cytochrome P450 3A4

Effect of glutathione on homo- and heterotropic cooperativity in cytochrome P450 3A4

Interactions of Endosulfan and Methoxychlor Involving CYP3A4 and CYP2B6 in Human HepaRG Cells

“Test Tube Cetaceans”: From the Evaluation of Susceptibility to the Study of Genotoxic Effects of Different Environmental Contaminants Using Cetacean Fibroblast Cell Cultures

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