title: Intracerebroventricularly and systemically delivered inhibitor of brain CYP2B (C8-Xanthate), even following chlorpyrifos exposure, reduces chlorpyrifos activation and toxicity in male rats.
abstract: Chlorpyrifos is a pesticide that is metabolically activated to chlorpyrifos oxon (acetylcholinesterase inhibitor) primarily by the cytochrome P450 2B (CYP2B) enzyme subfamily in the liver and brain. We have previously shown that intracerebroventricular pretreatment with a CYP2B inhibitor, C8-Xanthate, can block chlorpyrifos toxicity. Here, we assessed whether delayed introduction of C8-Xanthate would still reduce toxicity and whether peripheral administration of C8-Xanthate could also inhibit chlorpyrifos activation in the brain and block toxicity. Male rats (N = 4-5/group) were either pretreated with C8-Xanthate (40 μg intracerebroventricular or 5 mg/kg intraperitoneal), or vehicle (ACSF or saline, respectively), 24 h before chlorpyrifos treatment (125 mg/kg subcutaneous) and then treated daily with inhibitor or vehicle until 7 days post-chlorpyrifos treatment. Additional groups received vehicle pretreatment, switching to C8-Xanthate 1, 2, 3, or 4 days after chlorpyrifos and then continuing with daily C8-Xanthate treatment until 7 days post-chlorpyrifos treatment. Neurotoxicity was assessed at baseline (before chlorpyrifos) and then daily after chlorpyrifos, using behavioral assessments (e.g., gait score). Neurochemical assays (e.g., serum and brain chlorpyrifos) were performed at the end of study. Pretreatment with C8-Xanthate completely prevented chlorpyrifos toxicity, and delayed introduction of C8-Xanthate reduced toxicity, even when started up to 4 days after chlorpyrifos treatment. Discontinuation of C8-Xanthate treatment 7 days post-chlorpyrifos treatment did not result in the reappearance of toxicity, tested through 10 days after chlorpyrifos treatment. These findings suggest that CYP2B inhibitor treatment, even days after chlorpyrifos exposure, and using a peripheral delivery route, may be useful as a therapeutic approach to reduce chlorpyrifos toxicity.
authors.affiliation: Centre for Addiction and Mental Health (CAMH) and Departments of Pharmacology and Toxicology, and Psychiatry, University of Toronto, Toronto, Ontario, Canada M5S1A8.
authors.forename: Jibran Younis
authors.initials: JY
authors.lastname: Khokhar
authors.affiliation: Centre for Addiction and Mental Health (CAMH) and Departments of Pharmacology and Toxicology, and Psychiatry, University of Toronto, Toronto, Ontario, Canada M5S1A8 r.tyndale@utoronto.ca.
authors.forename: Rachel Fynvola
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D004390:Chlorpyrifos / Q000097:blood / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000633:toxicity*; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D020258:Neurotoxicity Syndromes / Q000201:enzymology / Q000517:prevention & control*; D017208:Rats, Wistar; D013871:Thiones / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D013871:Thiones; D019362:Cytochrome P-450 CYP2B1; D000110:Acetylcholinesterase; D004390:Chlorpyrifos
keywords: brain metabolism; cytochrome P450; neurotoxicity; pesticide poisoning