Differential induction of hepatic CYP enzymes by tobacco products and e-cigarettes: recommendation to rethink smoking status in clinical pharmacology.

Smoking status is often recorded as "Yes/No", but this binary approach overlooks the complexity of tobacco use and limits the precision of clinical data interpretation. Cigarette smoke is a known inducer of cytochrome P450 (CYP) enzymes, yet effects of other tobacco products on drug interactions remain poorly understood. This study addresses the gap by evaluating CYP1A1, CYP1A2, CYP2B6, CYP2C8 and CYP3A4 induction in primary human hepatocytes by 6 cigarette brands, 1 heated tobacco product (HTP), 6 cigar brands, 2 smokeless tobacco brands, and 3 e-cigarette brands (20 flavors). Cigarettes and cigars induced CYP1A1 strongest (4-29-fold mRNA; 29-95-fold enzyme activity), but also mRNA of CYP1A2 (4-10-fold), CYP2B6 (2-18-fold) and CYP3A4 (3-18-fold). HTPs demonstrated weaker CYP1A1 induction than cigarettes (3-4-fold mRNA, 6-16-fold enzyme activity), at 10-times higher concentrations, what clearly distinguishes them from cigarettes. Smokeless tobacco led to stronger mRNA induction of CYP1A2 (12-26-fold) than CYP1A1 (4-14-fold). E-cigarettes induced mRNA of CYP3A4 (2-108-fold), CYP2B6 (3-39-fold), and CYP2C8 (2-14-fold) more strongly than CYP1A1/CYP1A2 (2-7-fold), with brand-dependent differences for CYP3A4 and CYP2C8 (p < 0.01). Relevance of e-cigarette interactions was supported by CYP2B6 and CYP3A4 induction on enzyme activity and protein expression levels. Nicotine content did not influence induction outcome. These product-specific differences underscore that tobacco products should be distinguished in clinical pharmacology. It is highly recommended to collect detailed tobacco product use data in clinical studies, as provided in this work in an example. This would enable targeted in vitro testing of prevalent products, population specific trial planning and improve clinical data interpretation.