Title : Characterization of Differential Tissue Abundance of Major Non-CYP Enzymes in Human - Basit_2020_Mol.Pharm_17_4114 |
Author(s) : Basit A , Neradugomma NK , Wolford C , Fan PW , Murray B , Takahashi RH , Khojasteh SC , Smith BJ , Heyward S , Totah RA , Kelly EJ , Prasad B |
Ref : Mol Pharm , 17 :4114 , 2020 |
Abstract :
The availability of assays that predict the contribution of cytochrome P450 (CYP) metabolism allows for the design of new chemical entities (NCEs) with minimal oxidative metabolism. These NCEs are often substrates of non-CYP drug-metabolizing enzymes (DMEs), such as UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), carboxylesterases (CESs), and aldehyde oxidase (AO). Nearly 30% of clinically approved drugs are metabolized by non-CYP enzymes. However, knowledge about the differential hepatic versus extrahepatic abundance of non-CYP DMEs is limited. In this study, we detected and quantified the protein abundance of eighteen non-CYP DMEs (AO, CES1 and 2, ten UGTs, and five SULTs) across five different human tissues. AO was most abundantly expressed in the liver and to a lesser extent in the kidney; however, it was not detected in the intestine, heart, or lung. CESs were ubiquitously expressed with CES1 being predominant in the liver, while CES2 was enriched in the small intestine. Consistent with the literature, UGT1A4, UGT2B4, and UGT2B15 demonstrated liver-specific expression, whereas UGT1A10 expression was specific to the intestine. UGT1A1 and UGT1A3 were expressed in both the liver and intestine; UGT1A9 was expressed in the liver and kidney; and UGT2B17 levels were significantly higher in the intestine than in the liver. All five SULTs were detected in the liver and intestine, and SULT1A1 and 1A3 were detected in the lung. Kidney abundance was the most variable among the studied tissues, and overall, high interindividual variability (>15-fold) was observed for UGT2B17, CES2 (intestine), SULT1A1 (liver), UGT1A9, UGT2B7, and CES1 (kidney). These differential tissue abundance data can be integrated into physiologically based pharmacokinetic (PBPK) models for the prediction of non-CYP drug metabolism and toxicity in hepatic and extrahepatic tissues. |
PubMedSearch : Basit_2020_Mol.Pharm_17_4114 |
PubMedID: 32955894 |
Basit A, Neradugomma NK, Wolford C, Fan PW, Murray B, Takahashi RH, Khojasteh SC, Smith BJ, Heyward S, Totah RA, Kelly EJ, Prasad B (2020)
Characterization of Differential Tissue Abundance of Major Non-CYP Enzymes in Human
Mol Pharm
17 :4114
Basit A, Neradugomma NK, Wolford C, Fan PW, Murray B, Takahashi RH, Khojasteh SC, Smith BJ, Heyward S, Totah RA, Kelly EJ, Prasad B (2020)
Mol Pharm
17 :4114