This study defined the role oxidant injury plays in mediating hepatic injury caused by alcohol ingestion and viral infection, and to determine whether antioxidant vitamins modulate this effect. Specifically, I took advantage of a recently characterized approach to the quantitative assessment of free radical generation in vivo - measurement of isoprostanes - to address the hypothesis that free radical(FR) generation occurs in overt models of alcohol induced liver injury and is suppressed by antioxidant vitamin intake. I compared this marker of in vivo generation of FRs with an established ex vivo assay of oxidative injury - measurement of conjugated dienes. In addition, I explored the theory that vasoconstriction mediated by thromboxane A2 results in exacerbation of hepatic injury and that while the enzymatically produced metabolite of thromboxane A2 is reduced by aspirin administration there is no alteration in isoprostane excretion. We have recently shown that patients with both alcohol induced liver disease and hepatitis C induced cirrhosis have increased levels of oxidative stress as measured by urinary 8-epi PGF2 formation when compared with age and gender matched healthy controls. The source of the increased 8-epi PGF2 biosynthesis is unclear. Alcoholics are traditionally thought to consume a diet deficient in antioxidant vitamins. This study addressed the effect of antioxidant vitamin administration on this marker of oxidative injury in patients with established cirrhosis. Vasoconstriction of blood vessels supplying the liver leading to intrahepatic hypoxia has been proposed as one mechanism involved in the pathogenesis of alcoholic liver disease. Other investigators have proposed that thromboxanes acting via the thromboxane/ PGH2 receptors, promote liver injury in the ethanol fed rats by causing vasoconstriction. I measured levels of 11 - dehydro - TxB2, the urinary metabolite of thromboxane A2 in the same group of patients with established liver disease both before and after dosing with aspirin. Free radicals are generated during enzyme turnover and the induction of the cytochrome P450 isoform, CYP2E1, has been implicated as a source of FR generation during alcohol consumption. Similarly, FRs may be generated as a byproduct of enzyme activation upon cellular stimulation. Activation of platelets and neutrophils is a feature of cirrhosis and both may result in FR generation. Additional to its generation by a free radical catalyzed process, 8-epi PGF2 may also be formed as a minor product of cyclooxygenase turnover. This study addresses the hypothesis that this pathway contributes trivially to overall biosynthesis of the compound in vivo by showing no alteration in urinary 8-epi PGF2 excretion or conjugated diene formation following the administration of aspirin, a cyclooxygenase inhibitor, to patients with established liver disease.

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Khalili, Mandana; Shuhart, Margaret C; Lombardero, Manuel et al. (2018) Relationship Between Metabolic Syndrome, Alanine Aminotransferase Levels, and Liver Disease Severity in a Multiethnic North American Cohort With Chronic Hepatitis B. Diabetes Care 41:1251-1259
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