Does genetic variation in a bitter taste receptor gene alter early smoking behaviours in adolescents and young adults?

BACKGROUND AND AIMS: Variation in the TAS2R38 taste receptor gene alters the ability to taste bitter compounds. We tested whether TAS2R38 variation influences early smoking behaviours in adolescence, a critical period of acquisition when taste may influence the natural course of tobacco use. DESIGN AND PARTICIPANTS: Observational study (Nicotine Dependence in Teens [NDIT]). Cox proportional hazards models were conducted using data from European ancestry adolescent participants who initiated smoking during follow-up (n = 219, i.e. incident smokers). In young adulthood, cross-sectional analyses were restricted to European ancestry self-reported current smokers at age 24 (n = 148). SETTING: Montréal, Canada. MEASUREMENTS: In adolescents, the rates of attaining early smoking milestones were estimated for tasters {PAV diplotypes (i.e. PAV/PAV or PAV/AVI)} versus non-tasters {AVI diplotype (i.e. AVI/AVI)}. In young adults, associations between tasting status and a nicotine intake biomarker (cotinine + 3'hydroxycotinine) and past-week cigarette consumption were assessed. FINDINGS: Among incident smokers, similar rates to first whole cigarette were found between the diplotype groups (hazard ratio [HR], 1.05; 95% confidence interval (CI), 0.75-1.48; P = 0.765). However, smokers with the PAV (vs AVI) diplotypes attained monthly smoking more rapidly (HR, 1.55; 95% CI, 1.04-2.32; P = 0.033) and had faster conversion to three different measures of tobacco dependence (International Classification of Diseases: HR, 2.29; 95% CI, 0.99-5.28; P = 0.052; modified Fagerström Tolerance Questionnaire: HR, 3.02, 95% CI, 1.04-8.79; P = 0.043; Hooked on Nicotine Checklist: HR, 1.87; 95% CI, 0.98-3.60; P = 0.059). At age 24, those with PAV (vs AVI) diplotypes had higher mean cotinine + 3'hydroxycotinine (197 vs 143 ng/mL; P = 0.053). CONCLUSIONS: Adolescents with a genetic variation increasing their ability to taste bitter compounds appear to escalate more quickly to monthly smoking and tobacco dependence during adolescence and have higher nicotine intake in young adulthood versus those without that genetic variation.

Intracerebroventricularly and systemically delivered inhibitor of brain CYP2B (C8-Xanthate), even following chlorpyrifos exposure, reduces chlorpyrifos activation and toxicity in male rats.

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.