Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Rat brain CYP2B-enzymatic activation of chlorpyrifos to the oxon mediates cholinergic neurotoxicity. 2228 24

Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans.
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PMID:Impact of nicotine metabolism on nicotine's pharmacological effects and behavioral responses: insights from a Cyp2a(4/5)bgs-null mouse. 2404 21