International Journal of Scientific Research and Engineering Development

Non-cytochrome P450 (non-CYP) drug-metabolizing enzymes (DMEs)—including aldehyde oxidase (AO), carboxylesterases (CES1 and CES2), multiple UDP-glucuronosyltransferases (UGTs), and sulfotransferases (SULTs)—play a crucial role in the metabolism of nearly 30% of clinically approved drugs. However, comprehensive data comparing their abundance across human tissues remains limited. In this study, the protein levels of eighteen non-CYP DMEs were measured across five human tissues: liver, kidney, small intestine, heart, and lung. Aldehyde oxidase was highest in liver, with modest levels in kidney, and undetectable in intestine, heart, and lung. CES1 was most abundant in liver, while CES2 was enriched in the small intestine. UGT1A4, UGT2B4, and UGT2B15 were liver-specific; UGT1A10 was intestine-specific; UGT1A1 and UGT1A3 were present in both liver and intestine; UGT1A9 was detected in liver and kidney; and UGT2B17 levels were significantly higher in intestine compared to liver. All five SULT isoforms were found in liver and intestine, with SULT1A1 and SULT1A3 also present in lung. Moreover, kidney expression showed considerable variability. Notable interindividual variability (>15-fold) was observed for UGT2B17, intestinal CES2, hepatic SULT1A1, UGT1A9, UGT2B7, and renal CES1. These data are valuable for integrating non-CYP metabolism into physiologically based pharmacokinetic (PBPK) modeling to predict tissue-specific drug metabolism and toxicity.