Exposure to a Heated Tobacco Product Aerosol Is Associated with Lower Activity of Hepatic Cytochrome P450 Enzymes and Reduced Alteration in Clozapine Metabolism Than Exposure to Cigarette Smoke

      Bovard, D.; Renggli, K.; Marescotti, D.; Majeed, S.; Pak, C.; Iskandar, A.; Luettich, K.; Frentzel, S.; Hoeng, J.; Peitsch, M. C.

      Conference date
      Mar 3, 2021
      Conference name
      6th German Pharm-Tox Summit

      The main mechanism behind drug interactions with cigarette smoke (CS) involves activation of hepatic cytochrome P450 (CYP) isoenzymes by the polycyclic aromatic hydrocarbons present in CS. Activation of these enzymes can alter the metabolism of other drugs, potentially affecting their pharmacologic response.

      This study aimed to evaluate the impact of exposure to aerosol generated from Tobacco Heating System 2.2 (THS 2.2; Philip Morris International) on human liver xenobiotic metabolism and subsequent drug metabolism, compared with the impact of exposure to CS. We exposed liver spheroids composed of HepaRG cells to various concentrations of culture medium bubbled through with THS 2.2 or CS aqueous fractions (AF). After exposure for 48 or 96 h, the viability and xenobiotic metabolism of the tissues were analyzed. At 0.8 puffs/mL and just after 48 h of exposure, hepatotoxicity was observed with the CS AF but not with THS 2.2. The activity of 8 CYP enzymes was then measured by liquid chromatography–mass spectrometry (LC–MS) in liver spheroids exposed for 96 h to subtoxic doses of THS 2.2 and CS AF. Notably, exposure to the CS fraction caused a dose-dependent increase in the activity of CYP1A1/1B1, CYP1A2, CYP2A6, and CYP2B6 enzymes; but, it inhibited CYP3A4 activity. At a comparable concentration, exposure to the THS 2.2 aerosol fraction resulted in smaller changes in CYP activity relative to those observed with CS. Liver spheroids exposed to THS 2.2 or CS AF were then coincubated for 48 h with a subtoxic dose of clozapine, an antipsychotic drug. The levels of 7 clozapine metabolites were then measured by LC–MS. CS AF exposure was characterized by a reduction in the levels of 6 clozapine metabolites relative to the untreated condition or to THS 2.2 AF exposure (at a similar concentration as the CS aqueous fraction). Similar effects of the THS 2.2 AF on clozapine metabolism were observable at doses 32 times lower than CS.

      In conclusion, CS AF exposure of human liver spheroids resulted in increased hepatoxicity, increased CYP activity, and altered clozapine metabolism relative to the untreated condition. This latest observation is line with the clozapine pharmacodynamics changes observed in smokers. In contrast, THS 2.2 AF exposure resulted in reduced hepatotoxicity and smaller changes in liver xenobiotic metabolism and clozapine metabolism relative to exposure to similar concentrations of the CS AF.