(T0930-02-08) Alteration of Drug Metabolizing Enzyme and Transporter Expression Mediated by Electronic Cigarette Exposure: Implication in Drug Interaction

Purpose: Despite the prevalent perception about electronic cigarettes (e-Cigs) as a safe alternative for tobacco smoke, growing concern related to potential toxic impacts warrants adequate investigation. Several studies have demonstrated a drug-tobacco interaction effect of tobacco smoking by alteration of the expression and activity of drug metabolizing enzymes and transporters. This results in altered pharmacokinetics of selected drugs and subsequent alteration of pharmacological responses of several classes of drugs including antipsychotics, antidepressants, anticoagulants, bronchodilators, β blockers, opioids, antihypertensives, and antiarrhythmics. Due to this potential drug-tobacco interaction, dose adjustments can be required to avoid adverse drug reaction or to attain optimal pharmacological responses. However, no such data is available with reference to e-Cig exposure. Due to the noticeable growth in e-Cig usage among adolescents and adults, it has become critical to study the impact of e-Cig smoking on expression and activity of drug metabolizing enzymes (phase I and phase II) and drug transporters (influx and efflux). Hence, the aim of our study is to evaluate the effect of e-Cig exposure on the expression and activity of drug metabolizing enzymes and drug transporters both in brain and liver.

Methods: For this study, adult C57BL/6J male mice were exposed to 3R4F research grade tobacco cigarette or commercially available Juul e‐Cig vapor (5% nicotine) for 14 days. Nicotine and cotinine concentration in plasma were measured after 1 day and 14 days exposure by LC-MS/MS method. Expression of major drug metabolizing enzymes, cytochrome P450 (CYP1A2) and UDP-glucuronosyltransferase (UGT), drug influx/uptake transporters (organic anion transporting polypeptide or OATP) and drug efflux transporters or ATP binding cassette (ABCC4, ABCB1, ABCG2) were evaluated in brain collected from exposed and control mice using western blotting.

Results: Reduced body weight was observed in TS and Juul exposed offspring compared to control (P < 0.05). Higher concentrations of nicotine and cotinine in plasma samples were observed in Juul exposed mice compared to TS exposed mice (P < 0.05). Increased expression of CYP1A2 enzyme was also observed in the brain tissue of Juul exposed mice compared to TS and control (P < 0.05). However, no difference has been observed in case of UGT enzyme expression among control, TS and Juul. Additionally, reduced expression of ABCC4 (MRP4) was observed in TS and Juul compared to control (P < 0.05). On the other hand, increased expression of ABCB1(PGP/MDR1) was observed in both groups (TS and Juul) compared to the control (P < 0.05). No significant difference has been observed in ABCG2 (BCRP) and OATP expression level among control, TS and Juul.

Conclusion: Our findings suggest that e-Cig exposure affects the expression level of drug metabolizing enzymes and drug transporters which may play a pivotal role in drug interaction study. Our ongoing work includes evaluation of e-Cig exposure on hepatic enzymes as well as hepatic transporters in both in-vitro and in-vivo model.

Acknowledgements:

Funding: NIH R01DA049737 and R01DA02912.
No conflict of interest.


Plasma nicotine and cotinine concentration after 1 day and 14 days exposure to tobacco smoke (TS) or e-Cigarette (Juul) by LC-MS/MS


Expression of CYP1A2 and UGT enzymes in brain samples collected from control, tobacco smoke (TS) and e-Cigarette (Juul) exposed mice.


Expression of major efflux transporters (ABCB1,ABCC4 and ABCG2) in brain samples collected from control, tobacco smoke (TS) and e-Cigarette (Juul) exposed mice.