Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice.

Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24-96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol-fed mice. Inflammation, measured by TNFα mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure.

Bedaquiline metabolism: enzymes and novel metabolites.

Bedaquiline is a recently approved drug for the treatment of multidrug-resistant tuberculosis. Adverse cardiac and hepatic drug reactions to bedaquiline have been noted in clinical practice. The current study investigated bedaquiline metabolism in human hepatocytes using a metabolomic approach. Bedaquiline N-demethylation via CYP3A4 was confirmed as the major pathway in bedaquiline metabolism. In addition to CYP3A4, we found that both CYP2C8 and CYP2C19 contributed to bedaquiline N-demethylation. The Km values of CYP2C8, CYP2C19, and CYP3A4 in bedaquiline N-demethylation were 13.1, 21.3, and 8.5 µM, respectively. We also identified a novel metabolic pathway of bedaquiline that produced an aldehyde intermediate. In summary, this study extended our knowledge of bedaquiline metabolism, which can be applied to predict and prevent drug-drug interactions and adverse drug reactions associated with bedaquiline.

Weight gain among women in the late reproductive years.

BACKGROUND: Given the impact of obesity on mortality and morbidity in women, we evaluated correlates of weight gain in women ages 35-47 years. METHODS: Three hundred and thirty-six African American and Caucasian American women, randomly selected from among urban residents aged 35-47 years and pre-menopausal at baseline, were included in the prospective cohort study. Participants were followed over a 4-year period. Baseline measures included anthropometric variables, socio-demographic factors, measures of anxiety, depressed mood, quality of life, and self-reported measures of diet, vigorous physical activity, alcohol consumption and cigarette smoking. Hormone measurements were obtained during the follicular phase of the menstrual cycle. Weight gain was assessed by comparing the baseline weight with weight measured at the end of the 4-year period. RESULTS: Over 25% of the cohort gained > or =10 lb during follow-up. Five of the 14 women (36%) who were considered menopausal gained weight. Women aged 45-47 were 61% less likely to gain > or =10 lb compared with women aged 35-39 [odds ratio (OR) = 0.39, 95% confidence interval (CI) 0.18-0.87]. Depressed mood was a major correlate of weight gain (OR = 1.9, 95% CI 1.09-3.31). Other psychological measures, including anxiety and quality of life, were similarly correlated with weight gain. No association was detected for levels of sex hormones or self-reported measures of physical activity. Most recalled dietary factors were not predictive of subsequent weight gain in our population. CONCLUSIONS: In this population-based sample of women aged 35-47 years, psychological factors were the major predictors of gaining > or =10 lb during a 4-year follow-up period. Few of the other measures, including baseline hormone values, were correlated with subsequent weight gain. These findings suggest that screening for depression and anxiety may be important clinical assessments to identify women at increased risk of substantial weight gain.