The Effect of Chlorpyrifos-Oxon and other Xenobiotics on the Human Cytochrome P450-Dependent Metabolism of Naphthalene and DEET

Abstract

Chlorpyrifos-oxon (CPO), a metabolite of chlorpyrifos, is a potent inhibitor of acetylcholinesterase and, although the neurotoxicological impact of this organophosphorus compound has been broadly studied both in vitro and in vivo, there are few studies of metabolic interactions of CPO with other xenobiotics. CPO significantly activated the production of 1-naphthol (5-fold), 2-naphthol (10-fold), trans-1,2-dihydro-1,2-naphthalenediol (1.5-fold), and 1,4-naphthoquinone from naphthalene by human liver microsomes (HLM). It was further demonstrated that the production of naphthalene metabolites by CYP2C8, 2C9*(1), 2C19, 2D6*(1), 3A4, 3A5, and 3A7 was activated by CPO, while the production of naphthalene metabolites by CYP1A1, 1A2, 1B1, and 2B6 was inhibited by CPO. CPO inhibited CYP1A2 production of naphthalene metabolites, while activating their production by CYP3A4. Similarly, CPO inhibited the production of N,N-diethyl-m-hydroxymethylbenzamide (BALC) from DEET by human liver microsomes, but activated the production of N-ethyl-m-toluamide (ET) from this substrate. CYP2B6, the most efficient isoform for BALC production, was inhibited by CPO, while CYP3A4, the most efficient isoform for ET production, was activated by CPO. CPO inhibited CYP2B6 production of both BALC and ET from DEET, but activated CYP3A4 production of ET, while inhibiting CYP3A4 BALC production. CPO appears to facilitate the binding of naphthalene to CYP3A4. This metabolic activation is independent of cytochrome b5, suggesting that activation of CYP3A4 by CPO is associated with a conformational change of the isoform rather than facilitating electron transfer.

Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker

“…Furthermore, serial and/or combined exposures to multiple pesticides have potential to alter enzyme activities and the resulting excretion of BCP. Cho et al, 2007, suggest that chlorpyrifos and profenofos have the potential to inhibit the catalytic activity of CYP2B6 and CYP2C19, which also metabolizes chlorpyrifos (Foxenberg et al, 2007). Essentially no CYP 2B6 activity remained after in vitro chlorpyrifos or profenofos treatment, while 49 and 43 percent of the respective CYP2C19 activity remained after chlorpyrifos and profenofos pretreatment of HLMs (Abass et al, 2009).…”

Human Variation and Risk Assessment: Microarray and Other Studies Utilizing Human Hepatocytes and Human Liver Subcellular Preparations

“…Recently, we have demonstrated activation of the 6β‐hydroxylation of testosterone by human CYP3A4 by pyridostigmine bromide (Table ). More recently , studies of interactions of chlorpyrifos oxon (CPO) during the metabolism of naphthalene by human CYPs revealed a complex situation. CPO significantly activated the production of 1‐naphthol (fivefold), 2‐naphthol (10‐fold), and trans‐1,2‐dihydro‐1,2‐naphalenediol (1.5‐fold) by human liver microsomes although some individual isoforms were activated and others inhibited.…”

Deet

“…The metabolism of DEET, when administered in combination with other environmental chemicals, has been the subject of several recent studies and reviews (Cho et al, 2007;Hodgson, 2008). These investigations have generally been based upon in vitro experiments using human hepatic microsomes.…”