Assistant Director of The USC Research Center For Liver Diseases
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.
Ji C, Shinohara M, Vance D, Than TA, Ookhtens M, Chan C, Kaplowitz N. 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
Steiner AZ, Chang L, Ji Q, Ookhtens M, Stolz A, Paulson RJ, Stanczyk FZ. 3alpha-Hydroxysteroid dehydrogenase type III deficiency: a novel mechanism for hirsutism. J Clin Endocrinol Metab. 2008 Apr; 93(4):1298-303. View in: PubMed
Ji Q, Chang L, Stanczyk FZ, Ookhtens M, Sherrod A, Stolz A. 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
Lou H, Ookhtens M, Stolz A, Kaplowitz N. 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