nitrophenols and Alcoholism

Alcohol Use Disorder (AUD) is a significant public health issue in the United States. It affects millions of individuals and their families and contributes to substantial societal and economic burdens. Despite the availability of some pharmacological treatments, there is still a pressing need to develop more effective therapeutic strategies to address the diverse range of symptoms and challenges associated with AUD. Catechol-O-methyltransferase (COMT) inhibition recently emerged as a promising new approach to treating AUD due to its potential to improve cognitive effects commonly associated with AUD. Tolcapone, an FDA-approved COMT inhibitor, has shown some promise for treating AUD; however, its ability to decrease drinking in ethanol-dependent rats has not been well-established. In this study, we evaluated the effects of tolcapone on operant, oral ethanol self-administration in non-dependent and dependent rats, and in rats that self-administered oral saccharin. To induce dependence, rats underwent the chronic intermittent exposure to vapor model, and their drinking levels were assessed during acute withdrawal from ethanol. Our results demonstrated that tolcapone attenuated responding for ethanol in dependent rats only, without affecting self-administration in non-dependent rats or rats self-administering saccharin. Moreover, we found that tolcapone was differentially effective in different estrous phases in female rats. These findings suggest that COMT inhibition, specifically using tolcapone, may be a valuable pharmacotherapy for treating AUD, particularly in individuals who are physically dependent on alcohol. Further research is needed to elucidate the precise mechanisms underlying the observed effects and to assess the potential of COMT inhibitors in a broader population of individuals with AUD.

Topics: Alcoholism; Animals; Benzophenones; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Enzyme Inhibitors; Ethanol; Female; Humans; Nitrophenols; Rats; Saccharin; Tolcapone

Rates of glucuronidation and sulfation of 7-hydroxycoumarin were studied in perfused livers from normal chow-fed rats, or in livers from rats that had been fed liquid control or ethanol-containing diets. During infusion of 100 microM 7-hydroxycoumarin, rates of glucuronidation were similar in livers from chow-fed or control diet rats, but were 34% less in livers from ethanol-fed rats. These rates of glucuronidation in perfused livers could not be explained by changes of UDP-glucuronyltransferase activity, which was highest in hepatic microsomes from ethanol-treated rats and lowest in microsomes from chow-fed rats. The low rates of glucuronidation in livers from ethanol-treated rats were correlated with low hepatic concentrations of UDP-glucuronic acid, which were less than 70% of the levels measured in the other treatment groups. However, the diminished UDP-glucuronic acid levels could not be explained by alterations in adenine nucleotides, NAD+/NADH ratios, glycogen, UDP-glucose, or activity of UDP-glucose dehydrogenase. Rates of sulfation declined during prolonged 7-hydroxycoumarin infusion in livers from ethanol-treated rats, but not in livers from rats that had received the control diet. Similarly, hepatic concentrations of adenosine-3'-phosphate 5'-sulfatophosphate (PAPS) also decreased with time only in livers from ethanol-treated rats. Thus, chronic ethanol feeding impairs glucuronidation and sulfation in perfused livers as a result of diminished availability of the required cofactors for these conjugation pathways.

Topics: Adenosine Triphosphate; Alcoholism; Animals; Arylsulfotransferase; Female; Gluconeogenesis; Glucuronosyltransferase; Lactates; Liver; Nitrophenols; Phosphoadenosine Phosphosulfate; Pyruvates; Pyruvic Acid; Rats; Sulfurtransferases; Umbelliferones

Topics: Alcoholic Intoxication; Alcoholism; Bilirubin; Fatty Liver; Female; Glucuronates; Humans; Liver; Male; Microscopy, Electron; Microsomes, Liver; Mitochondria, Liver; Nitrophenols; Transferases

Topics: Alcoholism; Biliary Tract Diseases; Bilirubin; Biopsy, Needle; Chronic Disease; Coumarins; Glucuronates; Glucuronidase; Hemochromatosis; Hepatitis; Hepatitis A; Hexosyltransferases; Humans; Hyperbilirubinemia, Hereditary; Jaundice, Chronic Idiopathic; Liver; Liver Cirrhosis; Liver Diseases; Nitrophenols; Phenolphthaleins; Structure-Activity Relationship; Uridine Diphosphate Sugars