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      RAD-140 Drug-Induced Liver Injury

      case-report

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          Abstract

          Background: RAD-140, one of the novel selective androgen receptor modulators (SARMs), has potent anabolic effects on bones and muscles with little androgenic effect. Despite the lack of approval for its clinical use, RAD-140 is readily accessible on the consumer market. Hepatotoxicity associated with the use of SARMs has only rarely been reported in the literature.

          Case Report: A 24-year-old male presented with a 2-week history of diffuse abdominal pain, scleral icterus, pruritus, and jaundice. Prior to presentation, he had been taking the health supplement RAD-140 for muscle growth for 5 weeks. He had a cholestatic pattern of liver injury, with a peak total bilirubin of 38.5 mg/dL. Liver biopsy was supportive of a diagnosis of RAD-140–associated liver injury characterized pathologically by intracytoplasmic and canalicular cholestasis with minimal portal inflammation. Symptoms and liver injury resolved after cessation of the offending agent.

          Conclusion: To date, only select descriptions of the potential hepatoxicity associated with the use of SARMs, including RAD-140, have been published. Given their potential hepatoxicity and ready availability on the consumer market, RAD-140 and other SARMs should be used judiciously and under close clinical supervision until further hepatic safety data become available.

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          Most cited references16

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          Hepatobiliary transporters and drug-induced cholestasis.

          Drug-induced liver injury is an important clinical problem with significant morbidity and mortality. Whereas for most hepatocellular forms of drug-induced hepatic injury the underlying pathophysiological mechanism is poorly understood, there is increasing evidence that cholestatic forms of drug-induced liver damage result from a drug- or metabolite-mediated inhibition of hepatobiliary transporter systems. In addition to their key role in determining hepatic drug exposure and clearance, the coordinated action of these transport systems is essential for bile formation and the biliary secretion of cholephilic compounds and xenobiotics. Any drug-mediated functional disturbance of these processes can lead to an intracellular accumulation of potentially harmful bile constituents and result in the development of cholestatic liver cell damage. In addition to direct drug-mediated inhibition of hepatocellular transport, function of these transporters can be altered by pre-existing hepatic disease and genetic factors, which contribute to the development of drug-induced cholestasis in susceptible individuals. This review summarizes current knowledge about the function of hepatobiliary uptake and efflux systems and discusses factors that might predispose to drug-induced cholestasis.
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            Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications

            Selective androgen receptor modulators (SARMs) differentially bind to androgen receptors depending on each SARM's chemical structure. As a result, SARMs result in anabolic cellular activity while avoiding many of the side effects of currently available anabolic steroids. SARMs have been studied in the treatment of breast cancer and cachexia and have also been used as performance-enhancing agents. Here, we evaluate and summarize the current literature on SARMs.
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              Hepatic transport of bile salts.

              The vectorial secretion of bile salts from blood into bile is a major driving force for bile formation. The basolateral hepatocyte membrane extracts bile salts from sinusoidal blood via Na(+)-dependent and Na(+)-independent membrane transporters. Na(+)-dependent uptake of bile salts is mediated by the Na(+)-taurocholate co-transporting polypeptide, a 51-kDa protein that is exclusively expressed in hepatocytes. Na(+)-independent uptake of bile salts is mediated by the organic anion transporting polypeptides, a superfamily of multispecific bile salt and amphipathic substrate transporters. Within the hepatocyte, bile salts are bound to cytosolic proteins and traverse the cell mainly by diffusion. Transport across the canalicular membrane is the rate-limiting step in overall hepatocellular bile salt excretion and is mediated by the bile salt export pump (BSEP), a homologue of the P-glycoproteins or multidrug resistance gene products. BSEP is a vulnerable target for inhibition by estrogen metabolites, drugs such as cyclosporine A, and abnormal bile salt metabolites, all of which can cause retention of bile salts and consequently intrahepatic cholestasis. Canalicular efflux of divalent sulfated or glucuronidated bile salts is mediated by the multidrug resistance protein 2 (MRP2), which is strongly decreased in cholestasis. Decreased MRP2 expression leads to compensatory increases in the basolateral expression of MRP1 and MRP3, which mediate the sinusoidal efflux of divalent bile salt conjugates and other organic anions. Thus, the hepatocyte can regulate expression levels of individual bile salt transporters during cholestasis to evade hepatotoxic injury.
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                Author and article information

                Journal
                Ochsner J
                Ochsner J
                TOJ
                ochjnl
                The Ochsner Journal
                Academic Division of Ochsner Clinic Foundation
                1524-5012
                1524-5012
                Winter 2022
                Winter 2022
                : 22
                : 4
                : 361-365
                Affiliations
                [ 1 ]Department of Gastroenterology and Hepatology, VA Loma Linda Healthcare System , Loma Linda, CA
                [ 2 ]University of California , Riverside, Riverside, CA
                [ 3 ]Loma Linda University , Loma Linda, CA
                Author notes
                Address correspondence to Muhammad B. Hammami, MD, Department of Gastroenterology and Hepatology, VA Loma Linda Healthcare System, 26001 Redlands Blvd., Redlands, CA 92373. Tel: (909) 825-7084, ext. 2419. Email: bader.hammami@ 123456medsch.ucr.edu
                Article
                toj.22.0005
                10.31486/toj.22.0005
                9753945
                36561105
                56622c19-e5ae-4c02-83aa-ce33bcee8297
                ©2022 by the author(s); Creative Commons Attribution License (CC BY)

                © 2022 by the author(s); licensee Ochsner Journal, Ochsner Clinic Foundation, New Orleans, LA. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( creativecommons.org/licenses/by/4.0/legalcode) that permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

                History
                Page count
                Figures: 1, Tables: 2, References: 18, Pages: 5
                Categories
                Case Reports and Clinical Observations

                chemical and drug induced liver injury,enobosarm,lgd-4033,rad140

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