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Research ArticleArticle

Sex-, Age-, and Race/Ethnicity-Dependent Variations in Drug-Processing and NRF2-Regulated Genes in Human Livers

Jie Liu, Julia Yue Cui, Yuan-Fu Lu, J. Christopher Corton and Curtis D. Klaassen
Drug Metabolism and Disposition January 2021, 49 (1) 111-119; DOI: https://doi.org/10.1124/dmd.120.000181
Jie Liu
University of Kansas Medical Center, Kansas City, Kansas (J.L., J.Y.C., Y.-F.L., C.D.K.); Zunyi Medical University, Zunyi, China (J.L.,Y.-F.L.); University of Washington, Seattle, Washington (J.Y.C); and Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, North Carolina (J.L., J.C.C.)
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Julia Yue Cui
University of Kansas Medical Center, Kansas City, Kansas (J.L., J.Y.C., Y.-F.L., C.D.K.); Zunyi Medical University, Zunyi, China (J.L.,Y.-F.L.); University of Washington, Seattle, Washington (J.Y.C); and Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, North Carolina (J.L., J.C.C.)
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Yuan-Fu Lu
University of Kansas Medical Center, Kansas City, Kansas (J.L., J.Y.C., Y.-F.L., C.D.K.); Zunyi Medical University, Zunyi, China (J.L.,Y.-F.L.); University of Washington, Seattle, Washington (J.Y.C); and Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, North Carolina (J.L., J.C.C.)
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J. Christopher Corton
University of Kansas Medical Center, Kansas City, Kansas (J.L., J.Y.C., Y.-F.L., C.D.K.); Zunyi Medical University, Zunyi, China (J.L.,Y.-F.L.); University of Washington, Seattle, Washington (J.Y.C); and Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, North Carolina (J.L., J.C.C.)
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Curtis D. Klaassen
University of Kansas Medical Center, Kansas City, Kansas (J.L., J.Y.C., Y.-F.L., C.D.K.); Zunyi Medical University, Zunyi, China (J.L.,Y.-F.L.); University of Washington, Seattle, Washington (J.Y.C); and Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, North Carolina (J.L., J.C.C.)
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Abstract

Individual variations in xenobiotic metabolism affect the sensitivity to diseases. In this study, the impacts of sex, age, and race/ethnicity on drug-processing genes and nuclear factor erythroid 2–related factor 2 (NRF2) genes in human livers were examined via QuantiGene multiplex suspension array (226 samples) and quantitative polymerase chain reaction (qPCR) (247 samples) to profile the expression of nuclear receptors, cytochrome P450s, conjugation enzymes, transporters, bile acid metabolism, and NRF2-regulated genes. Sex differences were found in expression of about half of the genes, but in general the differences were not large. For example, females had higher transcript levels of catalase, glutamate-cysteine ligase catalytic subunit (GCLC), heme oxygenase 1 (HO-1), Kelch-like ECH-associated protein 1 (KEAP1), superoxide dismutase 1, and thioredoxin reductase-1 compared with males via qPCR. There were no apparent differences due to age, except children had higher glutamate-cysteine ligase modifier subunit (GCLM) and elderly had higher multidrug resistance protein 3. African Americans had lower expression of farnesoid X receptor (FXR) but higher expression of HO-1, Caucasians had higher expression of organic anion transporter 2, and Hispanics had higher expression of FXR, SULT2A1, small heterodimer partner, and bile salt export pump. An examination of 34 diseased and control human liver samples showed that compared with disease-free livers, fibrotic livers had higher NAD(P)H-quinone oxidoreductase 1 (NQO1), GCLC, GCLM, and NRF2; hepatocellular carcinoma had higher transcript levels of NQO1 and KEAP1; and steatotic livers had lower GCLC, GCLM, and HO-1 expression. In summary, in drug-processing gene and NRF2 genes, sex differences were the major findings, and there were no apparent age differences, and race/ethnicity differences occurred for a few genes. These descriptive findings could add to our understanding of the sex-, age-, and race/ethnicity-dependent differences in drug-processing genes as well as NRF2 genes in normal and diseased human livers.

SIGNIFICANCE STATEMENT In human liver drug-processing and nuclear factor erythroid 2–related factor 2 genes, sex differences were the main finding. There were no apparent differences due to age, except children had higher glutamate-cysteine ligase modifier subunit, and elderly had higher multidrug resistance protein 3. African Americans had lower expression of farnesoid X receptor (FXR) but higher expression of heme oxygenase 1, Caucasians had higher expression of organic anion transporter 2, and Hispanics had higher expression of FXR, small heterodimer partner, SULT2A1, and bile salt export pump.

Footnotes

    • Received July 15, 2020.
    • Accepted October 20, 2020.
  • Financial support for this research was provided by National Institutes of Health National Institute of Environmental Health Sciences Research [Grants ES013714, ES09716, and ES009649], National Institute of Diabetes and Digestive and Kidney Diseases Research [Grant DK081461], National Center for Research Resources [Grant RR-021940], and National Institutes of Health National Institute of Environmental Health Sciences Research Training [Grant ES-07079].

  • Disclaimer: The information in this document has been funded in part by the U.S. Environmental Protection Agency. It has been subjected to review by the Center for Computational Toxicology and Exposure and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

  • https://doi.org/10.1124/dmd.120.000181.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (1)
Drug Metabolism and Disposition
Vol. 49, Issue 1
1 Jan 2021
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Research ArticleArticle

Drug-Processing Genes and NRF2 in Human Liver

Jie Liu, Julia Yue Cui, Yuan-Fu Lu, J. Christopher Corton and Curtis D. Klaassen
Drug Metabolism and Disposition January 1, 2021, 49 (1) 111-119; DOI: https://doi.org/10.1124/dmd.120.000181

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Research ArticleArticle

Drug-Processing Genes and NRF2 in Human Liver

Jie Liu, Julia Yue Cui, Yuan-Fu Lu, J. Christopher Corton and Curtis D. Klaassen
Drug Metabolism and Disposition January 1, 2021, 49 (1) 111-119; DOI: https://doi.org/10.1124/dmd.120.000181
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