Alveolar Cytochrome P450 Mediates Butylated Hydroxytoluene-Induced Electrophilic Injury and Apoptosis.

Butylated hydroxytoluene (BHT) is a synthetic phenolic antioxidant utilized as a preservative in many products from foods to cosmetics. Population-based studies have detected BHT in the vast majority (>90%) of human specimens (serum, urine, fingernails) as well as home dust samples. Thus, BHT constitutes a ubiquitous environmental contaminant without obvious adverse health effects to humans. In contrast, exposure of mice to a single intraperitoneal dose of BHT triggers distal epithelial damage including loss of gas-exchanging alveolar type 1 epithelial cells, thus providing an invaluable tool to study alveolar repair and transient fibrosis. Presently, the molecular basis of BHT lung toxicity remains unknown. To address this, mouse lung single cell transcriptomic data were used to identify cytochrome P450 2B10 (CYP2B10) in AT1 cells as a BHT-activating enzyme. In cell culture systems, expression of CYP2B10 leads to marked BHT sensitization consistent with bioactivation of BHT into a toxic quinone methide. Targeted and proteome-wide experiments identify BHT-induced protein alkylation, DNA damage response, stress kinase activation and intrinsic apoptosis in a CYP2B10-dependent manner. Structure-activity relationship studies reveal the necessity of