Concentration dependent effects of tobacco particulates from different types of cigarettes on expression of drug metabolizing proteins, and benzo(a)pyrene metabolism in primary normal human oral epithelial cells

The ability of tobacco smoke (TS) to modulate phase I and II enzymes and affect metabolism of tobacco carcinogens is likely an important factor in its carcinogenicity. For the first time several types of TS particulates (TSP) were compared in different primary cultured human oral epithelial cells (NOE) for their abilities to affect metabolism of the tobacco carcinogen, (BaP) to genotoxic products, and expression of drug metabolizing enzymes. TSP from, reference filtered (2RF4), mentholated (MS), reference unfiltered, (IR3), ultra low tar (UL), and cigarettes that primarily heat tobacco (ECL) were tested. Cells pretreated with TSP concentrations of 0.2-10 μg/ml generally showed increased rates of BaP metabolism; those treated with TSP concentrations above 10 μg/ml showed decreased rates. Effects of TSPs were similar when expressed on a weight basis. Weights of TSP/cigarette varied in the order: MS ≈ IR3 > 2RF4 > ECL > UL. All TSPs induced the phase I proteins, cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1), phase II proteins, NAD(P)H dehydrogenase quinone 1 (NQO1), and microsomal glutathione S-transferase 1 (MGST1), and additionally, hydroxysteroid (17-beta) dehydrogenase 2 (HSD17B2), as assessed by qRT-PCR. The pattern of gene induction at probable physiological levels favored activation over detoxification.

► Tobacco smoke particulates (TSP) from different cigarettes exerted similar effects on primary human epithelial cells. ► Pretreatment of the cells with low levels of TSPs greatly enhanced their genotoxic metabolism of benzo(a)pyrene. ► Pretreatment of the cells with all TSPs greatly induced CYP1A1 and 1B1, and less so, NAD(P)H dehydrogenase quinone 1 (NQO1). ► All TSPs induced hydroxysteroid (17-beta) dehydrogenase 2 (HSD17B2), which plays a role in estrogen synthesis.