Faculty

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Murad Ookhtens, PhD
Associate Professor of Medicine
Assistant Director of The USC Research Center For Liver Diseases
Medicine
HMR 615 Health Sciences Campus Los Angeles
+1 323 442 1783

Overview

My research program, funded by NIH, is focused on delineating certain putative, critical interrelationships between the "regulation of hepatic and interorgan oxidant (redox) state" and "development and aging". Specifically, I study the developmental and age-related changes in hepatic and interorgan "synthesis, transport and turnover" of "sulfur amino acids and thiol-disulfides methionine, cysteine, cystine and glutathione (GSH)." The latter is a major "antioxidant" against "free radicals," in particular "radical oxygen species (ROS)." I study the mechanistic and quantitative aspects and regulation of these processes, using "tracer-kinetic methods," combined with "mathematical modeling, computer analysis, fitting and simulation." GSH is vital peptide that plays a critical role in the detoxification of ROS, which are estimated to routinely constitute about 3-5% by-products of normal oxidative metabolism.

The cumulative, irreversible damage caused by ROS to cellular structure and function has been proposed as a key mechanism of aging, with increasing evidence mounting in support of it. All cells are capable and synthesize GSH with the liver synthesizing it at the highest of rates and exporting essentially all of it to plasma (and some to bile), as practically the sole source for the latter. Through circulating blood plasma (interorgan), GSH and its extracellular breakdown products cysteine and cystine, the liver provides the latters to all extrahepatic tissues as precursors for GSH synthesis. I am studying the following specific and critical aspects of GSH metabolism as function of age. (1) Mechanisms of changes in the kinetics of hepatic sinusoidal and canalicular GSH efflux. (2) Mechanisms of changes in hepatic GSH turnover. (3) Hepatic availability of precursor sulfur amino acids, cysteine and methionine. (4) Hepatocellular maximal synthetic capacity for GSH. (5) Changes in hepatic mitochondrial GSH pool size and transport of cytosolic GSH to mitochondria. (6) Response of interorgan GSH pool size and turnover to my previously-delineated age-dependent decline in sinusoidal GSH efflux. The data from these experiments are analyzed by mathematical (multi-compartmental or other) models to interpret and integrate the findings into a comprehensive model of hepatic and interorgan GSH and thiol-disulfide turnover in aging.

Publications

Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments. PLoS Comput Biol. 2016 Dec; 12(12):e1005253. View in: PubMed

Effect of transgenic extrahepatic expression of betaine-homocysteine methyltransferase on alcohol or homocysteine-induced fatty liver. Alcohol Clin Exp Res. 2008 Jun; 32(6):1049-58. View in: PubMed

3alpha-Hydroxysteroid dehydrogenase type III deficiency: a novel mechanism for hirsutism. J Clin Endocrinol Metab. 2008 Apr; 93(4):1298-303. View in: PubMed

Impaired dihydrotestosterone catabolism in human prostate cancer: critical role of AKR1C2 as a pre-receptor regulator of androgen receptor signaling. Cancer Res. 2007 Feb 1; 67(3):1361-9. View in: PubMed

Chelerythrine stimulates GSH transport by rat Mrp2 (Abcc2) expressed in canine kidney cells. Am J Physiol Gastrointest Liver Physiol. 2003 Dec; 285(6):G1335-44. View in: PubMed

Radiation inactivation studies of hepatic sinusoidal reduced glutathione transport system. Biochim Biophys Acta. 2000 Apr 5; 1464(2):207-18. View in: PubMed

Novel properties of hepatic canalicular reduced glutathione transport revealed by radiation inactivation. Am J Physiol. 1998 May; 274(5 Pt 1):G923-30. View in: PubMed

Role of the liver in interorgan homeostasis of glutathione and cyst(e)ine. Semin Liver Dis. 1998; 18(4):313-29. View in: PubMed

Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: effect of membrane physical properties and S-adenosyl-L-methionine. Hepatology. 1997 Sep; 26(3):699-708. View in: PubMed

Evidence that interference with binding to hepatic cytosol binders can inhibit bile acid excretion in rats. Hepatology. 1996 Jun; 23(6):1642-9. View in: PubMed

Plasma membrane and mitochondrial transport of hepatic reduced glutathione. Semin Liver Dis. 1996 May; 16(2):147-58. View in: PubMed

GSH transporters: molecular characterization and role in GSH homeostasis. Biol Chem Hoppe Seyler. 1996 May; 377(5):267-73. View in: PubMed

Role of two recently cloned rat liver GSH transporters in the ubiquitous transport of GSH in mammalian cells. J Clin Invest. 1996 Mar 15; 97(6):1488-96. View in: PubMed

Developmental changes in plasma thiol-disulfide turnover in rats: a multicompartmental approach. Am J Physiol. 1994 Aug; 267(2 Pt 2):R415-25. View in: PubMed

Changes in plasma glutathione concentrations, turnover, and disposal in developing rats. Am J Physiol. 1994 Mar; 266(3 Pt 2):R979-88. View in: PubMed

Bidirectional membrane transport of intact glutathione in Hep G2 cells. Am J Physiol. 1993 Dec; 265(6 Pt 1):G1128-34. View in: PubMed

Selective induction by phenobarbital of the electrogenic transport of glutathione and organic anions in rat liver canalicular membrane vesicles. J Biol Chem. 1993 May 25; 268(15):10836-41. View in: PubMed

Transport of glutathione at blood-brain barrier of the rat: inhibition by glutathione analogs and age-dependence. J Pharmacol Exp Ther. 1992 Dec; 263(3):964-70. View in: PubMed

Canalicular transport of reduced glutathione in normal and mutant Eisai hyperbilirubinemic rats. J Biol Chem. 1992 Jan 25; 267(3):1667-73. View in: PubMed

Zonal distribution of cysteine uptake in the perfused rat liver. J Biol Chem. 1992 Jan 5; 267(1):192-6. View in: PubMed

Mechanism of changes in hepatic sinusoidal and biliary glutathione efflux with age in rats. Am J Physiol. 1991 Oct; 261(4 Pt 1):G648-56. View in: PubMed

Effect of indomethacin on the uptake, metabolism and excretion of 3-oxocholic acid: studies in isolated hepatocytes and perfused rat liver. Biochim Biophys Acta. 1991 Jul 30; 1084(3):247-50. View in: PubMed

Impaired uptake of glutathione by hepatic mitochondria from chronic ethanol-fed rats. Tracer kinetic studies in vitro and in vivo and susceptibility to oxidant stress. J Clin Invest. 1991 Feb; 87(2):397-405. View in: PubMed

Hormonal regulation of glutathione efflux. J Biol Chem. 1990 Sep 25; 265(27):16088-95. View in: PubMed

Evidence for carrier-mediated transport of glutathione across the blood-brain barrier in the rat. J Clin Invest. 1990 Jun; 85(6):2009-13. View in: PubMed

Inhibition of GSH efflux from rat liver by methionine: effects of GSH synthesis in cells and perfused organ. Am J Physiol. 1990 Jun; 258(6 Pt 1):G967-73. View in: PubMed

Effect of amiodarone on non-deiodinative pathway of thyroid hormone metabolism. Acta Endocrinol (Copenh). 1990 Feb; 122(2):249-54. View in: PubMed

The use of isolated perfused liver in studies of biological transport processes. Methods Enzymol. 1990; 192:485-95. View in: PubMed

Effects of chronic ethanol feeding on rat hepatocytic glutathione. Relationship of cytosolic glutathione to efflux and mitochondrial sequestration. J Clin Invest. 1989 Apr; 83(4):1247-52. View in: PubMed

Therapeutic tolerance, hemodynamic effects, and oral dose kinetics of dilazep dihydrochloride in hypertensive patients. J Pharm Sci. 1989 Apr; 78(4):281-4. View in: PubMed

The role of cytoplasmic proteins in hepatic bile acid transport. Annu Rev Physiol. 1989; 51:161-76. View in: PubMed

Effect of membrane potential and cellular ATP on glutathione efflux from isolated rat hepatocytes. Am J Physiol. 1988 Oct; 255(4 Pt 1):G403-8. View in: PubMed

Inhibition of glutathione efflux in the perfused rat liver and isolated hepatocytes by organic anions and bilirubin. Kinetics, sidedness, and molecular forms. J Clin Invest. 1988 Aug; 82(2):608-16. View in: PubMed

Fat pad triacylglycerol fatty acid loss and oxidation as indices of total body triacylglycerol fatty acid mobilization and oxidation in starving mice. Biochim Biophys Acta. 1988 Feb 4; 958(2):188-98. View in: PubMed

Effect of age on the sinusoidal release of hepatic glutathione from the perfused rat liver. Biochem Pharmacol. 1987 Nov 15; 36(22):4015-7. View in: PubMed

Cyclical oxidation-reduction of the C3 position on bile acids catalyzed by 3 alpha-hydroxysteroid dehydrogenase. II. Studies in the prograde and retrograde single-pass, perfused rat liver and inhibition by indomethacin. J Clin Invest. 1987 Sep; 80(3):861-6. View in: PubMed

Effect of chronic ethanol feeding on rat hepatocytic glutathione. Compartmentation, efflux, and response to incubation with ethanol. J Clin Invest. 1987 Jul; 80(1):57-62. View in: PubMed

Transport and metabolism of extracellular free fatty acids in adipose tissue of fed and fasted mice. J Lipid Res. 1987 May; 28(5):528-39. View in: PubMed

Trans-stimulation and driving forces for GSH transport in sinusoidal membrane vesicles from rat liver. Biochem Biophys Res Commun. 1987 Feb 27; 143(1):377-82. View in: PubMed

Mechanism of inhibition of glutathione efflux by methionine from isolated rat hepatocytes. Am J Physiol. 1986 Sep; 251(3 Pt 1):G354-61. View in: PubMed

Inhibition of fatty acid incorporation into adipose tissue triglycerides in Ehrlich ascites tumor-bearing mice. Cancer Res. 1986 Feb; 46(2):633-8. View in: PubMed

Kinetics of glutathione efflux from isolated rat hepatocytes. Am J Physiol. 1986 Feb; 250(2 Pt 1):G236-43. View in: PubMed

Gamma-glutamylcysteine: a substrate for glutathione S-transferases. Biochem Pharmacol. 1985 Oct 15; 34(20):3643-7. View in: PubMed

Sinusoidal efflux of glutathione in the perfused rat liver. Evidence for a carrier-mediated process. J Clin Invest. 1985 Jan; 75(1):258-65. View in: PubMed

The regulation of hepatic glutathione. Annu Rev Pharmacol Toxicol. 1985; 25:715-44. View in: PubMed

Effects of chronic administration of amiodarone on kinetics of metabolism of iodothyronines. Endocrinology. 1984 Nov; 115(5):1710-6. View in: PubMed

Inhibition of glutathione efflux from isolated rat hepatocytes by methionine. J Biol Chem. 1984 Aug 10; 259(15):9355-8. View in: PubMed

Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am J Physiol. 1984 Jul; 247(1 Pt 2):R146-53. View in: PubMed

Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications. J Am Coll Cardiol. 1984 Jul; 4(1):111-6. View in: PubMed

Incomplete free fatty acid oxidation by ascites tumor cells under low oxygen tension. Am J Physiol. 1983 Jan; 244(1):R84-92. View in: PubMed

Essential and nonessential fatty acid oxidation in mice bearing Ehrlich ascites carcinoma. Lipids. 1982 Feb; 17(2):65-71. View in: PubMed

Turnover and transport of plasma very-low-density lipoprotein triglycerides in mice bearing Ehrlich ascites carcinoma. Cancer Res. 1982 Jan; 42(1):132-8. View in: PubMed

Compartmental analysis of linoleate and palmitate turnover in a murine carcinoma. Cancer Res. 1980 Jul; 40(7):2447-54. View in: PubMed

Evaluation of impaired triglyceride fatty acid transport and oxidation for the detection of cancer in mice. Cancer Res. 1979 Dec; 39(12):5118-23. View in: PubMed

Fatty acid oxidation to H2O by Ehrlich ascites carcinoma in mice. Cancer Res. 1979 Mar; 39(3):973-80. View in: PubMed

Regulation of plasma-free fatty acid mobilization by dietary glucose in Ehrlich ascites tumor-bearing mice. Cancer Res. 1978 Aug; 38(8):2372-7. View in: PubMed

Competition for host essential and nonessential fatty acids by Ehrlich ascites carcinoma in mice. Cancer Res. 1977 Jul; 37(7 Pt 1):2218-25. View in: PubMed

Fluctuations of plasma glucose and insulin in conscious dogs receiving glucose infusions. Am J Physiol. 1974 Apr; 226(4):910-9. View in: PubMed

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