Nathan Cherrington, PhD
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.
Our group has made significant strides in identifying liver-specific disturbances in the expression and function of xenobiotic biotransformation enzymes and membrane drug transporters. Importantly, these molecular alterations in the expression and function of drug transporters and biotransformation enzymes lead to in vivo perturbations in the disposition of numerous xenobiotics.
Therefore, we suggest that patients with NAFLD present as a subpopulation of individuals that are at higher risk for developing ADRs, due to aberrant disposition of drugs and other xenobiotics. Specifically, our group has documented individual differences in ADME genes and proteins, such as metabolizing enzymes and transporters that cause a profound alteration in the pharmacokinetics, overall exposure, and toxicity of clinically relevant drugs and xenobiotics.
BS, Brigham Young University, 1993, Zoology
PhD, North Carolina State University, 1997, Toxicology
PD, University of Kansas Medical Center, 1998-2002, Toxicology
Clarke JD, Dzierlenga AL, Nelson NR, Li H, Werts S, Goedken MJ, Cherrington NJ. Mechanism of Altered Metformin Distribution in Nonalcoholic Steatohepatitis. Diabetes. 2015 Sep;64(9):3305-13.
Clarke JD, Cherrington NJ. Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability. Pharmacol Ther. 2015 Jul;151:99-106.
Canet MJ, Merrell MD, Hardwick RN, Betaille AM, Campion SN, Ferreira DW, Manautou JE, A-Kader HH, Erickson RP, Cherrington NJ. Altered Regulation of Hepatic Efflux Transporters Disrupts Acetaminophen Disposition in Pediatric Nonalcoholic Steatohepatitis. Drug Metab Dispos. 2015 Jun;43(6):829-35.
Lake AD, Novak P, Shipkova P, Aranibar N, Robertson D, Reily MD, Lehman-McKeeman LD, Vaillancourt RR, Cherrington NJ. Branched Chain Amino Acid Metabolism Profiles in Progressive Human Nonalcoholic Fatty Liver Disease. Amino Acids 2014; 47(3):603-15.
Dzierlenga AL, Clarke JD, Hargraves TL, Ainslie GR, Vanderah TW, Paine MF, Cherrington N. Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis. J Pharmacol Exp Ther. 2015 Mar; 352(3):462-70.
Canet MJ, Hardwick RN, Lake AD, Dzierlenga AL, Clarke JD, Goedken MJ, Cherrington NJ. Renal Xenobiotic Transporter Expression is Altered in Multiple Experimental Models of Nonalcoholic Steatohepatitis. Drug Metab Dispos. 2015 Feb; 43(2):266-72.
Canet MJ, Merrell MD, Harder BG, Maher JM, Wu T, Lickteig AJ, Jackson JP, Zhang DD, Yamamoto M, Cherrington NJ. Identification of a Functional Antioxidant Response Element within the Eighth Intron of the Human ABCC3 Gene. Drug Metab Dispos. 2015 Jan; 43(1):93-9.
Hardwick RN, Clarke JD, Lake AD, Canet MJ, Anumol T, Street SM, Merrell MD, Goedken MJ, Snyder SA, Cherrington NJ. Increased Susceptibility to Methotrexate-Induced Toxicity in Nonalcoholic Steatohepatitis. Toxicol Sci. 2014 Nov 1; 142(1):45-55.
Canet MJ, Cherrington NJ. Drug disposition alterations in liver disease: extrahepatic effects in cholestasis and nonalcoholic steatohepatitis. Expert Opin Drug Metab Toxicol. 2014 Sep; 10(9):1209-19
Klein DM, Wright SH, Cherrington NJ. Xenobiotic transporter expression along the male genital tract. Reprod Toxicol. 2014 Aug; 47:1-8.
Clarke JD, Hardwick RN, Lake AD, Lickteig AJ, Goedken MJ, Klaassen CD, Cherrington NJ. Synergistic interaction between genetics and disease on pravastatin disposition. J Hepatol. 2014 Jul; 61(1):139-47.
Clarke J, Hardwick R, Lake A, Canet M, Cherrington NJ. Experimental nonalcoholic steatohepatitis increases exposure to simvastatin hydroxy acid by decreasing hepatic organic anion transporting polypeptide expression. J Pharmacol Exp Ther. 2014 Mar; 348(3):452-8.
Canet MJ, Hardwick RN, Lake AD, Dzierlenga AL, Clarke JD, Cherrington NJ. Modeling Human Nonalcoholic Steatohepatitis-Associated Changes in Drug Transporter Expression Using Experimental Rodent Models. Drug Metab Dispos. 2014 Apr; 42(4):586-95
Clarke JD, Sharapova T, Lake AD, Blomme E, Maher J, Cherrington NJ. Circulating microRNA 122 in the methionine- and choline-deficient mouse model of non-alcoholic steatohepatitis. J Appl Toxicol. 2014 Jun; 34(6):726-32.
Klein, D.M., S.H. Wright, and N.J. Cherrington, Localization of Multidrug Resistance-Associated Proteins Along the Blood-testis Barrier in Rat, Macaque, and Human Testis. Drug Metab Dispos, 2014 Jan; 42(1):89-93.
Lake, A.D., P. Novak, R.N. Hardwick, B. Flores-Keown, F. Zhao, W.T. Klimecki, and N.J. Cherrington, The Adaptive Endoplasmic Reticulum Stress Response to Lipotoxicity in Progressive Human Nonalcoholic Fatty Liver Disease. Toxicol Sci, 2014 Jan; 137(1):26-35.
Clarke, J.D., P. Novak, A.D. Lake, P. Shipkova, N. Aranibar, D. Robertson, P.L. Severson, M.D. Reily, B.W. Futscher, L.D. Lehman-McKeeman, and N.J. Cherrington, Characterization of Hepatocellular Carcinoma Related Genes and Metabolites in Human Nonalcoholic Fatty Liver Disease. Dig Dis Sci, 2014 Feb; 59(2):365-74.
Merrell MD, Cherrington NJ. Drug metabolism alterations in nonalcoholic fatty liver disease. Drug Metab Rev. 2011 May 25. [Epub ahead of print] PMID: 21612324
Hardwick RN, Fisher CD, Canet MJ, Lake A, and Cherrington NJ. Diversity in antioxidant response enzymes in progressive stages of human nonalcoholic fatty liver disease. Drug Metab. Dispos. 2010 2010 Dec;38(12):2293-301. PMID: 20805291.
Fisher CD, Lickteig AJ, Augustine LM, Ranger-Moore J, Jackson JP, Ferguson SS, Cherrington NJ. Hepatic cytochrome P450 enzyme alterations in humans with progressive stages of non-alcoholic fatty liver disease. Drug. Metab. Dispos. 2009 Oct;37(10):2087-94. PMID: 19651758.
Beilke LD, Aleksunes LM, Olson ER, Besselsen DG, Klaassen CD, Dvorak K, Cherrington NJ. Decreased apoptosis during CAR-mediated hepatoprotection against lithocholic acid-induced liver injury in mice. Toxicol. Lett. 2009 Jul 10;188(1):38-44. PMID: 19433268.
Fisher CD, Lickteig AJ, Augustine LM, Oude Elferink RP, Besselsen DG, Erickson RP, Cherrington NJ. Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats. Eur. J. Pharmacol. 2009 Jun 24;613(1-3):119-27. PMID: 19358839.
Beilke LD, Aleksunes LM, Holland RD, Besselsen DG, Beger RD, Klaassen CD, Cherrington NJ. Constitutive androstane receptor-mediated changes in bile acid composition contributes to hepatoprotection from lithocholic acid-induced liver injury in mice. Drug Metab. Dispos. 2009 May;37(5):1035-45. PMID: 19196849.
Fisher CD, Jackson JP, Lickteig AJ, Augustine LM, Cherrington NJ. Drug metabolizing enzyme induction pathways in experimental non-alcoholic steatohepatitis. Arch. Toxicol. 2008 Dec;82(12):959-64. PMID: 18488193.
Merrell MD, Jackson JP, Augustine LM, Fisher CD, Slitt AL, Maher JM, Huang W, Moore DD, Zhang Y, Klaassen CD, Cherrington NJ. The Nrf2 activator oltipraz also activates the constitutive androstane receptor. Drug Metab. Dispos. 2008 Aug;36(8):1716-21. PMID: 18474683.
Beilke LD, Besselsen DG, Cheng Q, Kulkarni S, Slitt AL, Cherrington NJ. Minimal Role of Hepatic Transporters in the Hepatoprotection against LCA-Induced Intrahepatic Cholestasis. Toxicol. Sci. 2008 Mar;102(1):196-204. PMID: 18032408.
Lickteig AJ, Fisher CD, Augustine LM, and Cherrington NJ. Genes of the antioxidant response undergo up-regulation in a rodent model of nonalcoholic steatohepatitis. J. Biochem. Mol. Toxicol. 2007;21(4):216-20. PMID: 17721935.
Lickteig AJ, Fisher CD, Augustine LM, Aleksunes LM, Besselsen DG, Slitt AL, Manautou JE, and Cherrington NJ. Efflux transporter expression and acetaminophen metabolite excretion are altered in rodent models of non-alcoholic fatty liver disease. Drug Metab Dispos. 2007 Oct;35(10):1970-8. PMID: 17640958.
Lickteig AJ, Slitt AL, Arkan MC, Karin M, Cherrington NJ. Differential regulation of hepatic transporters in the absence of TNF-α, IL-1β and NF-κB in two models of cholestasis. Drug Metab Dispos. 2007 35(3):402-9. PMID: 17151194.