Nathan J Cherrington

Nathan J Cherrington

Professor, Pharmacology and Toxicology
Associate Dean, Research and Graduate Studies - College of Pharmacy
Director, Southwest Environmental Health Science Center
Professor, Public Health
Professor, Clinical Translational Sciences
Professor, BIO5 Institute
Primary Department
Department Affiliations
Contact
(520) 626-0219

Research Interest

Numerous drug-induced and environmental exposure-related toxicities are the result of inter-individual variation in the ADME processes of absorption, distribution, metabolism and elimination that control the fate of these compounds from the body. Alterations in these processes provide the mechanistic basis for individual variability in response to drugs and environmental exposures. A common perception is that variability in response is due to genetic polymorphisms within the drug metabolizing enzyme and transporter genes. While there are numerous examples of these differences that play a major role in the susceptibility of genetic subpopulations for specific toxicities, the potential for transient phenotypic conversion due to temporary environmental changes, such as inflammation and disease, are often overlooked.Due to the ensuing liver damage caused by the progressive stages of NAFLD, gene expression patterns can change dramatically resulting in a phenoconversion resembling genetic polymorphisms. Because the liver plays such a key role in the metabolism and disposition of xenobiotics, this temporary phenoconversion could lead to the inability of patients to properly metabolize and excrete drugs and environmental toxicants, increasing the risk of some adverse drug reactions and environmental toxicities.

Publications

Li, H., Clarke, J. D., Dzierlenga, A. L., Bear, J., Goedken, M. J., & Cherrington, N. J. (2017). In vivo cytochrome P450 activity alterations in diabetic nonalcoholic steatohepatitis mice. Journal of biochemical and molecular toxicology, 31(2).

Nonalcoholic steatohepatitis (NASH) has been identified as a source of significant interindividual variation in drug metabolism. A previous ex vivo study demonstrated significant changes in hepatic Cytochrome P450 (CYP) activity in human NASH. This study evaluated the in vivo activities of multiple CYP isoforms simultaneously in prominent diabetic NASH mouse models. The pharmacokinetics of CYP selective substrates: caffeine, losartan, and omeprazole changed significantly in a diabetic NASH mouse model, indicating attenuation of the activity of Cyp1a2 and Cyp2c29, respectively. Decreased mRNA expression of Cyp1a2 and Cyp2c29, as well as an overall decrease in CYP protein expression, was found in the diabetic NASH mice. Overall, these data suggest that the diabetic NASH model only partially recapitulates the human ex vivo CYP alteration pattern. Therefore, in vivo determination of the effects of NASH on CYP activity should be conducted in human, and more appropriate models are required for future drug metabolism studies in NASH.

Maher, J. M., Slitt, A. L., Cherrington, N. J., Cheng, X., & Klaassen, C. D. (2005). Tissue distribution and hepatic and renal ontogeny of the multidrug resistance-associated protein (MRP) family in mice. Drug Metabolism and Disposition, 33(7), 947-955.

PMID: 15802388;Abstract:

Analysis of the mouse genome has revealed eight multidrug resistance-associated (Mrp) transporters, with mouse homologs for all human MRPs except MRP8. Whereas MRP expression in tissues of humans and rats has been examined, no characterization exists for mice. Furthermore, the ontogeny of mouse Mrps is unknown, and such knowledge may be helpful in understanding age-related pharmacokinetics. Therefore, the purpose of this study was to quantitatively determine 1) expression of the Mrp family in 12 different tissues, 2) gender variations in Mrp expression in liver and kidney, and 3) whether Mrp expression is altered during development. Highest expression of the Mrp family members is as follows: Mrp1 in testes, ovary, and placenta; Mrp2 in intestine, followed by liver and kidney; Mrp3 in large intestine; Mrp4 in kidney; Mrp5 in brain, followed by lung and stomach; Mrp6 in liver; Mrp7 in testes, intestine, and kidney; and Mrp9 solely in testes. Gender differences in Mrp expression were observed: Mrp1, 3, and 4 in kidney, as well as Mrp1 and 4 in liver were female-predominant. Ontogeny of the four Mrps expressed in liver was as follows: Mrp2 and Mrp4 were expressed at adult levels at birth; Mrp3 reached adult levels at day 30, and Mrp6 was not expressed until day 10. In kidney, Mrp1 and Mrp5 were expressed at adult levels at birth, whereas Mrp2, 3, 4, and 6 generally increased over time. In conclusion, marked differences in expression of the individual Mrp family members exist in various tissues, with age, and with gender. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.

Ditzel, E. J., Li, H., Foy, C. E., Perrera, A. B., Parker, P., Renquist, B. J., Cherrington, N. J., & Camenisch, T. D. (2016). Altered Hepatic Transport by Fetal Arsenite Exposure in Diet-Induced Fatty Liver Disease. Journal of biochemical and molecular toxicology, 30(7), 321-30.

Non-alcoholic fatty liver disease can result in changes to drug metabolism and disposition potentiating adverse drug reactions. Furthermore, arsenite exposure during development compounds the severity of diet-induced fatty liver disease. This study examines the effects of arsenite potentiated diet-induced fatty liver disease on hepatic transport in male mice. Changes were detected for Mrp2/3/4 hepatic transporter gene expression as well as for Oatp1a4/2b1/1b2. Plasma concentrations of Mrp and Oatp substrates were increased in arsenic exposure groups compared with diet-only controls. In addition, murine embryonic hepatocytes and adult primary hepatocytes show significantly altered transporter expression after exposure to arsenite alone: a previously unreported phenomenon. These data indicate that developmental exposure to arsenite leads to changes in hepatic transport which could increase the risk for ADRs during fatty liver disease.

Yalcin, E. B., More, V., Neira, K. L., Lu, Z. J., Cherrington, N. J., Slitt, A. L., & King, R. S. (2013). Downregulation of sulfotransferase expression and activity in diseased human livers. Drug Metabolism and Disposition, 41(9), 1642-1650.

PMID: 23775849;PMCID: PMC3876809;Abstract:

Sulfotransferase (SULT) function has been well studied in healthy human subjects by quantifying mRNA and protein expression and determining enzyme activity with probe substrates. However, it is not well known if sulfotransferase activity changes in metabolic and liver disease, such as diabetes, steatosis, or cirrhosis. Sulfotransferases have significant roles in the regulation of hormones and excretion of xenobiotics. In the present study of normal subjects with nonfatty livers and patients with steatosis, diabetic cirrhosis, and alcoholic cirrhosis, we sought to determine SULT1A1, SULT2A1, SULT1E1, and SULT1A3 activity and mRNA and protein expression in human liver tissue. In general, sulfotransferase activity decreased significantly with severity of liver disease from steatosis to cirrhosis. Specifically, SULT1A1 and SULT1A3 activities were lower in disease states relative to nonfatty tissues. Alcoholic cirrhotic tissues further contained lower SULT1A1 and 1A3 activities than those affected by either of the two other disease states. SULT2A1, on the other hand, was only reduced in alcoholic cirrhotic tissues. SULT1E1 was reduced both in diabetic cirrhosis and in alcoholic cirrhosis tissues, relative to nonfatty liver tissues. In conclusion, the reduced levels of sulfotransferase expression and activity in diseased versus nondiseased liver tissue may alter the metabolism and disposition of xenobiotics and affect homeostasis of endobiotic sulfotransferase substrates. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Yu, A. M., Ingelman-Sundberg, M., Cherrington, N. J., Aleksunes, L. M., Zanger, U. M., Xie, W., Jeong, H., Morgan, E. T., Turnbaugh, P. J., Klaassen, C. D., Bhatt, A. P., Redinbo, M. R., Hao, P., Waxman, D. J., Wang, L., & Zhong, X. B. (2017). Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO). Acta pharmaceutica Sinica. B, 7(2), 241-248.

Variations in drug metabolism may alter drug efficacy and cause toxicity; better understanding of the mechanisms and risks shall help to practice precision medicine. At the 21st International Symposium on Microsomes and Drug Oxidations held in Davis, California, USA, in October 2-6, 2016, a number of speakers reported some new findings and ongoing studies on the regulation mechanisms behind variable drug metabolism and toxicity, and discussed potential implications to personalized medications. A considerably insightful overview was provided on genetic and epigenetic regulation of gene expression involved in drug absorption, distribution, metabolism, and excretion (ADME) and drug response. Altered drug metabolism and disposition as well as molecular mechanisms among diseased and special populations were presented. In addition, the roles of gut microbiota in drug metabolism and toxicology as well as long non-coding RNAs in liver functions and diseases were discussed. These findings may offer new insights into improved understanding of ADME regulatory mechanisms and advance drug metabolism research.