Effects of Nicotine Exposure on In Vitro Metabolism of Chlorpyrifos in Male Sprague-Dawley Rats

The routine use of tobacco products may modify key metabolizing systems, which will further impact the metabolism of environmental contaminants. The objective of this study was to quantify the effect of repeated in vivo exposures to nicotine, a major pharmacologically active component of cigarette smoke, on in vitro metabolism of chlorpyrifos (CPF). CPF is an organophosphorus (OP) insecticide that is metabolized by cytochrome P-450 (CYP450) to its major metabolites, chlorpyrifos-oxon (CPF-oxon) and 3,5,6-trichloro-2-pyridinol (TCP). Male Sprague-Dawley rats were dosed subcutaneously with 1 mg nicotine/kg for 1, 7, or 10 d. Rats were sacrificed 4 or 24 h after the last nicotine treatment, and liver microsomes were prepared. The microsomes were incubated with varying concentrations of CPF and the production of the metabolites CPF-oxon and TCP were measured. The metabolism of CPF to the active oxon metabolite did not show significant changes following repeated nicotine treatments, evidenced by the unchanged pseudo first-order clearance rate of Vmax/Kmapp. The Vmax describing the metabolism of CPF to the inactive metabolite, TCP was increased in 24-h postdosing groups, after both single and repeated treatments of nicotine. In contrast, the metabolism to TCP was unchanged in groups evaluated at 4 h (single or repeated) post nicotine dosing. Some basic marker substrate activities were also investigated to ensure that nicotine exerted effects on CYP450 activities. Total P450 reduced spectra were not altered by nicotine treatment, but marker substrate activities for CYP1A and CYP2E1 were increased at 24 h after the single treatment, and marker substrate activity for CYP2B was decreased 4 h after 7 d of treatment. Results of this in vitro study suggest that repeated nicotine exposure may result in altered metabolism of CPF. Future in vivo experiments based on these results need to be conducted to ascertain the impact of in vivo nicotine exposures on CPF metabolism in rats.