Human Hepatic Cytochrome P450-Specific Metabolism of Parathion and Chlorpyrifos

Abstract

ABSTRACT:Organophosphorus pesticides (OPs) remain a potential concern to human health because of their continuing worldwide use. Thiophosphorus OPs, once bioactivated by cytochromes P450 (P450s), form oxon metabolites, which are potent acetylcholinesterase inhibitors. This study investigated the rate of desulfation (activation) and dearylation (detoxification) of parathion and chlorpyrifos in human liver microsomes. In addition, recombinant human P450s were used to quantify, for the first time, the P450-specific kinetic variables (K m and V max ) for each compound for future use in refining human physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models of OP exposure. CYP1A2, 2B6, 2C9, 2C19, 3A4, 3A5, and 3A7 were found to be active to a widely varying degree in parathion metabolism, whereas all, with the exception of CYP2C9, were also found to be active in chlorpyrifos metabolism. P450-specific kinetic parameters for OP metabolism will be used with age-dependent hepatic P450 content to enhance PBPK/PD models so that OP exposures can be modeled to protect human health in different age groups.

Cytochrome P450 mRNA Expression in the Rodent Brain: Species-, Sex-, and Region-Dependent Differences

“…Biotransformation of these compounds by P450s can result in bioactivation or detoxication, and the balance between these activities influences the bioeffective dose, and thus the neurotoxic outcome, following environmental exposures, as shown in studies of humans and animal models (Foxenberg et al, 2007;Curran et al, 2011;Kim et al, 2011;Crane et al, 2012;Khokhar and Tyndale, 2012).…”

“…We also assessed the influence of sex and species on P450 expression profiles in the brain using the male mouse as the reference. We studied CYP2B (mouse CYP2B10/rat CYP2B1/2), CYP3A (mouse CYP3A11/rat CYP3A2), and CYP1A2 because these isoforms have been implicated in the metabolism of polychlorinated biphenyls (Kania-Korwel et al, 2008Curran et al, 2011), polybrominated diphenyl ethers (Erratico et al, 2013;Feo et al, 2013), and organophosphorus pesticides (Tang et al, 2001;Foxenberg et al, 2007). Two orphan P450s, CYP4X1 and CYP2S1 (Guengerich et al, 2010), were also included in this study because CYP2S1 is abundantly expressed in many extrahepatic tissues (Choudhary et al, 2003) and CYP4X1 is predominantly expressed in the rodent brain (Bylund et al, 2002;Al-Anizy et al, 2006).…”

“…The cytochrome P450 (P450) superfamily is a diverse group of enzymes that catalyze the oxidative metabolism of not only endogenous substrates but also xenobiotics, including environmental contaminants of significant public health concern that target the nervous system, including polychlorinated biphenyls, polybrominated diphenyl ethers, and organophosphorus pesticides (Ariyoshi et al, 1995;Foxenberg et al, 2007;Erratico et al, 2013;Feo et al, 2013). Biotransformation of these compounds by P450s can result in bioactivation or detoxication, and the balance between these activities influences the bioeffective dose, and thus the neurotoxic outcome, following environmental exposures, as shown in studies of humans and animal models (Foxenberg et al, 2007;Curran et al, 2011;Kim et al, 2011;Crane et al, 2012;Khokhar and Tyndale, 2012).…”

Enzymatic detoxification of organophosphorus pesticides and related toxicants

“…[116][117][118] CYPs in the human liver are generally involved in metabolizing pesticides, and, although a number of different isoforms are involved, CYP2B6 and CYP2C19 seem to be the most important. [117][118][119] The polymorphism found in this group of enzymes determines susceptibility to the toxic effects of pesticides. Furthermore, it is well known that pesticides can act as inducers of CYP isoforms in human tissues.…”

Chlorpyrifos- and chlorpyrifos oxon-induced neurite retraction in pre-differentiated N2a cells is associated with transient hyperphosphorylation of neurofilament heavy chain and ERK 1/2

“…The fetus is thought to be exposed mainly to oxons formed in the maternal tissues; the main enzyme responsible for oxon formation in humans CYP2B6 (Foxenberg et al 2007;Croom et al 2010) is present at relatively low levels in human placenta (Pelkonen et al 2006), suggesting that the placenta does not make a major contribution to oxon formation. However, although CYP2B6 is expressed at low levels in the human fetus compared to later stages of development (Croom et al 2009), the fact that paraoxonase 1 (PON 1) levels are also relatively low at this stage (Costa et al 2005) could allow some oxon formation and/or accumulation in fetal tissue.…”