Polychlorinated biphenyls (PCBs) interact with drug metabolism in vivo.

Polychlorinated biphenyls (PCBs) are widespread environmental contaminants that interfere with xenobiotic metabolism, primarily by modulating cytochrome P450 (CYP) enzymes. However, their pharmacokinetic consequences in exposed individuals remain poorly defined. Here, we investigated the impact of PCB exposure on CYP enzyme activity using a combined clinical pharmacokinetic and in vitro mechanistic approach. Ten occupationally PCB-exposed individuals from the German HELPcB cohort and ten controls received a CYP phenotyping cocktail to assess enzyme function (Clinical Trial Registry: DRKS00028922). Plasma drug and metabolite concentrations were quantified to evaluate CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A activity, considering genetically defined metabolizer status. PCB118 exposure was significantly associated with reduced CYP1A2 activity (R2 = 0.155, t = - 2.115, p = 0.049, β = - 0.446), indicating a decrease in CYP1A2 activity with higher PCB118 levels. This was further supported by in vitro assays demonstrating dose-dependent inhibition. In addition, PCB74 exposure showed a trend toward increased CYP2C9 activity, suggesting a potential inductive effect. Mechanistic studies revealed that PCB118 acts as both an inhibitor and a substrate of CYP1A2, generating reactive arene oxide intermediates that may contribute to mechanism-based inhibition. These findings challenge the traditional view of PCBs as merely chronic toxicants, showing that they can acutely alter drug metabolism and potentially impact drug efficacy and safety. Given the widespread presence of PCBs and other persistent organic pollutants, these results highlight the need to integrate environmental toxicant exposure into pharmacokinetic models to optimize drug therapy and minimize adverse effects.