Metabolism of Endosulfan-α by Human Liver Microsomes and Its Utility as a Simultaneous in Vitro Probe for CYP2B6 and CYP3A4

Casabar, Richard C.; Wallace, Andrew D.; Hodgson, Ernest; Rose, Randy L.

doi:10.1124/dmd.106.010199

Cited by 57 publications

(13 citation statements)

References 18 publications

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“…CYP3A4 and CYP2B6 are both implicated in metabolism of endosulfan and methoxychlor (Blizard et al, 2001;Casabar et al, 2006). We evaluated whether endosulfan, methoxychlor and their mixture could modulate their expression and/or activity after single and repeated exposure.…”

Section: Resultsmentioning

confidence: 99%

“…In the present work, we studied whether the two organochlorine pesticides endosulfan and methoxychlor could interact. In common with numerous other chemicals and endogenous substrates, endosulfan and methoxychlor are activators of two major nuclear receptors, pregnane X receptor (PXR) and/or constitutive androstane receptor (CAR) (Casabar et al, 2010;Kublbeck et al, 2011), and their major routes of metabolism involve cytochrome P450s CYP3A4 and CYP2B6, which are known to be regulated by the two nuclear receptors (Blizard et al, 2001;Casabar et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…CYP3A4 accounts for roughly 40% of the total cytochrome P450 in human liver microsomes, and metabolizes more than 50% of the clinically used drugs. CYP3A4 is also expressed in the small intestine, where it contributes to the first-pass elimination of many drugs [1][2][3][4] . The ability of CYP3A4 to metabolize numerous structurally unrelated compounds accounts for the large number of documented drug interactions associated with CYP3A4 inhibition.…”

Section: Introductionmentioning

confidence: 99%

Bufalin inhibits CYP3A4 activity in vitro and in vivo

Zhang

et al. 2009

Acta Pharmacol Sin

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Aim:To investigate the inhibitory interactions of bufalin and CYP3A4. Methods: Recombinant human CYP3A4 was incubated with bufalin in vitro. Bufalin was administered ig and iv to Wistar rats to further estimate its impact on CYP3A4, and midazolam was given to index the activity of CYP3A4. Results: The IC 50 of bufalin was 14.52 μmol/L. Bufalin affected CYP3A4 activity with increases in AUC 0-t and t 1/2 , and decreases in CL and the formation of 1-hydroxy-midazolam after ig or iv administration of midazolam (P<0.05). An increase in C max after ig bufalin administration (P<0.05) was observed. Conclusion: Bufalin showed a modest but significant inhibition of CYP3A4 both in vitro and in vivo. The likelihood of an interaction between bufalin and the CYP3A4-metabolized drugs in human might not be negated.

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“…CYP2B6 plays a major role in pesticides metabolism. CYP2B6 mediates herbicides Ndealkoxylation (Coleman et al, 2000); organophosphate insecticides desulfuration (Foxenberg et al, 2007;Mutch & Williams, 2006;Buratti et al, 2005;Leoni et al, 2008;Sams et al, 2000;); orghanochlorine and carbamate insecticides sulfoxidation (Abass et al, 2010;Casabar et al, 2006;; fungicide metalaxyl Odemethylation and lactone formation (Abass et al, 2007b).…”

Section: Cyp2b Subfamilymentioning

confidence: 99%

“…Detailed characteristics of several CYP3A4 substrates and inhibitors were summarized recently by Liu et al (Liu et al, 2007). The known pesticides mainly metabolized by CYP3A4 belong to several chemical groups such as, carbamate, phosphorothioate, chlorinated cyclodiene and neonicotinoid insecticides (Tang et al, 2002;Abass et al, 2010;Mutch & Williams, 2006;Schulz-Jander & Casida, 2002;Buratti et al, 2005;Sams et al, 2000;Casabar et al, 2006;Mutch et al, 2003;Usmani et al, 2004;Buratti et al, 2002;Buratti et al, 2003;Buratti & Testai, 2007;Butler and Murray, 1997), herbicides (Abass et al, 2007c;Coleman et al, 2000), fungicides (Abass et al, 2007b;Abass et al, 2009;Mazur et al, 2007), and organotin biocide (Ohhira et al, 2006). CYP3A5 mediates midazolam, alprazolam and mifepristone metabolism (Christopher Gorski et al, 1994;Galetin et al, 2004;Hirota et al, 2001;Huang et al, 2004;Khan et al, 2002;Williams et al, 2002).…”

Section: Cyp2e Subfamilymentioning

confidence: 99%

Do Cytochrome P450 Enzymes Contribute to the Metabolism of Xenobiotics in Human?

Abass¹,

Reponen²,

Turpeinen³

et al. 2010

Fungicides

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Metabolism of Endosulfan-α by Human Liver Microsomes and Its Utility as a Simultaneous in Vitro Probe for CYP2B6 and CYP3A4

Cited by 57 publications

References 18 publications

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

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

Bufalin inhibits CYP3A4 activity in vitro and in vivo

Do Cytochrome P450 Enzymes Contribute to the Metabolism of Xenobiotics in Human?

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