Chlorpyrifos is a commonly used
insecticide that can be metabolically activated by CYP2B to the
acetylcholinesterase inhibitor chlorpyrifos-oxon causing
cholinergic overstimulation and neurotoxicity. Rat brain extracts can also activate
chlorpyrifos in vitro, and the lack of circulating oxon in serum suggests that metabolic activation within the brain may be responsible for
chlorpyrifos neurotoxicity. Rats received intracerebroventricular (ICV)
injections of CYP2B mechanism-based inhibitors (MBI), once or repeatedly, followed by
chlorpyrifos (62.5-250 mg/kg sc). Rats were assessed for neurochemical (
acetylcholinesterase activity), physiological (temperature), and behavioral measures (e.g., gait, righting reflex, arousal, incline angles) at 4 hours 3 days after
chlorpyrifos treatment. ICV CYP2B MBIs increased brain
chlorpyrifos levels, decreased brain
chlorpyrifos-oxon levels, and attenuated the reduction in brain
acetylcholinesterase; there was no effect on serum
chlorpyrifos levels or
acetylcholinesterase activity reduction. Inhibition of brain
chlorpyrifos metabolism by CYP2B MBIs blocked centrally mediated
hypothermia but not peripherally mediated
hyperthermia. A single ICV MBI treatment significantly attenuated
chlorpyrifos neurotoxicity mediated behavioral outcomes at 1 day after
chlorpyrifos treatment with a gradual worsening of behavioral scores through day 3, suggesting a recovery of brain CYP2B activity and an increase in local
chlorpyrifos activation. Daily ICV MBI
injections attenuated neurotoxicity across all test days consistent with prolonged inhibition of brain
chlorpyrifos activation. Thus, rat brain CYP2B contributes significantly to
chlorpyrifos's neurotoxic effects. Variable human brain CYP2B levels, influenced by genetics and environmental exposures, may contribute to interindividual differences in neurotoxicity. Therapeutic inhibition of brain CYP2B could also be explored as a treatment for exposure to CYP2B-activated
neurotoxins.