Bioactivation of chlorpyrifos by CYP2B6 variants

Crane, Alice L.; Klein, Kathrin; Olson, James R.

doi:10.3109/00498254.2012.702246

Cited by 15 publications

(8 citation statements)

References 34 publications

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“…CYP2B6 has furthermore been found to be of importance in the metabolism of pesticides and other environmental chemicals and pollutants (Hodgson and Rose, 2007). In particular the bioactivating oxidation of the organophosphorus insecticides chlorpyrifos (Crane et al, 2012) and methyl parathion (Ellison et al, 2012a) to their more toxic oxon metabolites is mainly catalyzed by CYP2B6, a public health concern due to their worldwide use and documented human exposures (Ellison et al, 2012b). Further environmental substrates are the insecticide and endocrine disruptor methoxychlor, the extensively used insect repellent N , N -diethyl- m -toluamide (Das et al, 2008), profenofos and other pesticides (Abass and Pelkonen, 2012), as well as the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; Smith et al, 2003), aflatoxin B1 (Code et al, 1997), and others (Hodgson and Rose, 2007; Abass and Pelkonen, 2012).…”

Section: The Chemical Interaction Profile Of Cyp2b6mentioning

confidence: 99%

Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

Zanger¹,

Klein²

2013

Front. Genet.

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Cytochrome P450 2B6 (CYP2B6) belongs to the minor drug metabolizing P450s in human liver. Expression is highly variable both between individuals and within individuals, owing to non-genetic factors, genetic polymorphisms, inducibility, and irreversible inhibition by many compounds. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. CYP2B6 is one of the most polymorphic CYP genes in humans and variants have been shown to affect transcriptional regulation, splicing, mRNA and protein expression, and catalytic activity. Some variants appear to affect several functional levels simultaneously, thus, combined in haplotypes, leading to complex interactions between substrate-dependent and -independent mechanisms. The most common functionally deficient allele is CYP2B6*6 [Q172H, K262R], which occurs at frequencies of 15 to over 60% in different populations. The allele leads to lower expression in liver due to erroneous splicing. Recent investigations suggest that the amino acid changes contribute complex substrate-dependent effects at the activity level, although data from recombinant systems used by different researchers are not well in agreement with each other. Another important variant, CYP2B6*18 [I328T], occurs predominantly in Africans (4–12%) and does not express functional protein. A large number of uncharacterized variants are currently emerging from different ethnicities in the course of the 1000 Genomes Project. The CYP2B6 polymorphism is clinically relevant for HIV-infected patients treated with the reverse transcriptase inhibitor efavirenz, but it is increasingly being recognized for other drug substrates. This review summarizes recent advances on the functional and clinical significance of CYP2B6 and its genetic polymorphism, with particular emphasis on the comparison of kinetic data obtained with different substrates for variants expressed in different recombinant expression systems.

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Section: The Chemical Interaction Profile Of Cyp2b6mentioning

confidence: 99%

Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

Zanger¹,

Klein²

2013

Front. Genet.

Self Cite

278

220

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Stamou

Kania-Korwel

et al. 2013

Drug Metab Dispos

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Cytochrome P450 (P450) enzymes play a critical role in the activation and detoxication of many neurotoxic chemicals. Although research has largely focused on P450-mediated metabolism in the liver, emerging evidence suggests that brain P450s influence neurotoxicity by modulating local metabolite levels. As a first step toward better understanding the relative role of brain P450s in determining neurotoxic outcome, we characterized mRNA expression of specific P450 isoforms in the rodent brain. Adult mice (male and female) and rats (male) were treated with vehicle, phenobarbital, or dexamethasone. Transcripts for CYP2B, CYP3A, CYP1A2, and the orphan CYP4X1 and CYP2S1 were quantified in the liver, hippocampus, cortex, and cerebellum by quantitative (real-time) polymerase chain reaction. These P450s were all detected in the liver with the exception of CYP4X1, which was detected in rat but not mouse liver. P450 expression profiles in the brain varied regionally. With the exception of the hippocampus, there were no sex differences in regional brain P450 expression profiles in mice; however, there were marked species differences. In the liver, phenobarbital induced CYP2B expression in both species. Dexamethasone induced hepatic CYP2B and CYP3A in mice but not rats. In contrast, brain P450s did not respond to these classic hepatic P450 inducers. Our findings demonstrate that P450 mRNA expression in the brain varies by region, regional brain P450 profiles vary between species, and their induction varies from that of hepatic P450s. These novel data will be useful for designing mechanistic studies to examine the relative role of P450-mediated brain metabolism in neurotoxicity. IntroductionThe 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).Much of the research effort to characterize P450-mediated metabolism of neurotoxic compounds has focused on the liver. However, it is now evident that P450s are expressed in a number of extrahepatic tissues, including brain (Ding and Kaminsky, 2003;Ferguson and Tyndale, 2011). Although total P450 content in the human and rodent brain is generally significantly lower than that in the liver (Warner et al., 1988;Bhamre et al., 1992;Volk et al., 1995), recent evidence from rat studies demonstrates that P45...

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“…As mentioned above, CPF is initially "activated" in the liver into its oxon metabolite in a CYP-dependent metabolic reaction. In vitro studies with hepatic microsomes or purified enzymes from humans and/or rodents revealed that different CYP isozymes (e.g., human CYP2B6 and CYP1A2, rat CYP1A1, 2B1, and 3A1/2) are involved in the oxidative desulfurization of CPF (Crane, Klein, & Olson, 2012;Dalvi, Dalvi, & Lane, 2004;Foxenberg, McGarrigle, Knaak, Kostyniak, & Olson, 2007). Thereafter, both CPF and CPF oxon are rapidly hydrolyzed to 3,5,6-trichloro-2-pyridinol (3,5,6-TCP) followed by conjugation via both UDP-glucuronyl-transferases (UDPGTs) and glutathione transferases (GSTs) (Hodgson & Rose, 2006).…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo effects of chlorpyrifos and cypermethrin on blood cholinesterases in sheep

Larsen

Lifschitz

Lanusse

et al. 2019

Vet Pharm & Therapeutics

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The combination of the organophosphate (OP) chlorpyrifos (CPF) and the pyrethroid cypermethrin (CPM) is commonly marketed as pour‐on formulations for the control of sheep lice, ked, and blowflies. CPF irreversibly inhibits acetylcholinesterases (AChE), while pyrethroids are not AChE inhibitors. However, combinations of pyrethroids with OPs showed a highly synergistic effect on AChE inhibition. Thus, the aim of the current work was to evaluate in vitro and in vivo the inhibitory potency of both pesticides, alone and in combination with AChE and butyrylcholinesterase (BChE) activities in sheep blood. In vitro, IC50 values were similar after CPF or CPF plus CPM incubations. The pour‐on coadministration of recommended doses of CPF and CPM did not cause a significant inhibition of AChE and BChE in sheep blood. Only slight percentages of inhibition of their catalytic activities were observed when both drugs were given at 4‐fold higher dose rates. The lower systemic availability of topical administration of OPs in sheep may help to explain the lower degree of inhibition of blood AChE and BChE in vivo. The results emerged from this research are a further contribution to the knowledge of the risks of implementing higher dosage regimens of OPs‐containing antiparasitic formulations.

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Bioactivation of chlorpyrifos by CYP2B6 variants

Cited by 15 publications

References 34 publications

Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

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

In vitro and in vivo effects of chlorpyrifos and cypermethrin on blood cholinesterases in sheep

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