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• W4377029180 abstract "<b>Abstract ID 16149</b> <b>Poster Board 178</b> Hepatocytes are the key cell type in liver for biotransformation of drugs and other xenobiotics. The liver lobule is categorized into 3 zones: periportal (zone 1), midzonal (zone 2), and centrilobular (zone 3). There lacks a systematic characterization of the zonal distribution of drug-processing genes. Therefore, the goal of this study was to characterize the zonal distribution of drug metabolizing enzymes and transporters as well as their regulators in liver. Mouse single cell transcriptomic data (GSE192742) aligned to the mm10 reference genome were downloaded from the GEO database and subjected to zonal deconvolution. Filtering, normalization, clustering, and differential expression analyses were performed using Seurat (v4) in R (v4.1.1). Hepatocytes were identified from all the cells in the liver using known hepatocyte-specific marker genes. The hepatocytes were then assigned into one of the three zones using known zone-specific marker genes. Among the 102 mouse cytochrome P450s (Cyps), 50 were differentially enriched in the three zones. As expected, the majority of Cyps were enriched in zone 3: for example, <i>Cyp2e1</i>, which activates many hepatotoxicants was expressed 4-times higher in zone 3, and <i>Cyp7a1</i>, the rate limiting enzyme in bile acid synthesis was expressed 17-fold higher in zone 3 than zone 1. However, not all Cyps had higher expression in zone 3 than zone 1. For example, <i>Cyp2f2</i> and <i>Cyp2a4</i> were expressed 4.5- and 14-fold higher, respectively, in zone 1 than zone 3. Of the other phase-I enzymes, most aldehyde dehydrogenases were expressed more highly in zone 1 than zone 3; of the five flavin-containing monooxygenases, two were more highly expressed in the zone 2 and one in zone 1: and all six peroxidases were more highly expressed in zone 1. Phase-II conjugation enzymes such as the glucuronosyltransferases and glutathione-<i>S</i> transferases were more highly expressed in zone 3, whereas the sulfotransferases were enriched in zone 1. The hepatic xenobiotic uptake transporters were most highly expressed in zone 3 than zone 1: <i>Oatp1a1</i>, <i>1a4</i>, and <i>2b1</i> were 4-, 5-, and 9-fold more highly expressed in zone 3 than zone 1. The major canalicular efflux transporter <i>Mrp2</i> was 6-fold more highly expressed in zone 3 than zone 1. In contrast, the major bile acid transporters, namely, the basolateral uptake transporter <i>Ntcp</i> was evenly distributed among all three zones, whereas the canalicular efflux transporter <i>Bsep</i> was expressed higher in zones 2 and 3. The transcription factors known to regulate xenobiotic biotransformation, namely Ahr, CAR, PXR, PPARα, and Nrf2 were expressed 15-, 6-, 2.5-, 4.9-fold higher in zone 3 than zone 1 hepatocytes. In conclusion, our study has unveiled unique zonal specific expression patterns of major drug-processing genes and their regulators in hepatocytes. Because many hepatotoxicants require bioactivation, our findings lay the foundation for further understanding the mechanisms of zonal specific drug-induced liver injuries. This work was supported by the National Institutes of Health (NIH) (grants R01ES030197, and R01ES031098), the University of Washington Center for Exposures, Diseases, Genomics, and Environment (P30ES007033), Environmental Pathology/Toxicology Training Program (T32ES007032), Environmental Health and Microbiome Research Center, and the University of Washington Sheldon Murphy Endowment." @default.
• W4377029180 created "2023-05-19" @default.
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• W4377029180 date "2023-05-18" @default.
• W4377029180 modified "2023-09-29" @default.
• W4377029180 title "Deciphering the Zonal Distribution of Hepatic Drug Metabolizing Enzymes and Transporters in Mice by Single Cell Transcriptomics" @default.
• W4377029180 doi "https://doi.org/10.1124/jpet.122.161490" @default.
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