No abstract

Individuals with chronic excessive alcohol ingestion are put at the risk of acute and chronic pancreatitis. Underlying molecular mechanisms are unknown. Differential gene expression in the pancreas was profiled using mRNA differential display by comparison between control and ethanol-consuming rats. Male Wistar rats were fed with diets containing 6.7% (vol/vol) ethanol for 4 wk. A cDNA tag that was overexpressed in the pancreas of rats fed ethanol was isolated. A 723-bp cDNA was cloned from a rat pancreatic cDNA library, which encodes a novel rat mitochondrial ATP synthase subunit 9, isoform 3 (ATP5G3), which is homologous to a human ATP5G3 gene. Real-time PCR demonstrated that all three nuclear gene isoforms (ATP5G1, ATP5G2, and ATP5G3) were consistently upregulated in the pancreas of alcohol-consuming rats, parallel with mitochondrial injury. The cellular response to mitochondrial damage and metabolic stress may reflect an adaptive process for mitochondrial repair in pancreatic acinar cells during chronic ethanol ingestion.

ABSTRACT:These studies were designed to characterize the disposition and metabolism of atomoxetine hydrochloride [(؊)-N-methyl-␥-(2-methylphenoxy)benzenepropanamine hydrochloride; formerly know as tomoxetine hydrochloride] in Fischer 344 rats and beagle dogs. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the majority of its metabolites being excreted into the urine, 66% of the total dose in the rat and 48% in the dog. Fecal excretion, 32% of the total dose in the rat and 42% in the dog, appears to be due to biliary elimination and not due to unabsorbed dose. Nearly the entire dose was excreted within 24 h in both species. In the rat, low oral bioavailability was observed (F ‫؍‬ 4%) compared with the high oral bioavailability in dog (F ‫؍‬ 74%). These differences appear to be almost purely mediated by the efficient first-pass hepatic clearance of atomoxetine in rat. The biotransformation of atomoxetine was similar in the rat and dog, undergoing aromatic ring hydroxylation, benzylic oxidation (rat only), and Ndemethylation. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming O-glucuronide and O-sulfate (dog only) metabolites. Although subtle differences were observed in the excretion and biotransformation of atomoxetine in rats and dogs, the primary difference observed between these species was the extent of first-pass metabolism and the degree of systemic exposure to atomoxetine and its metabolites.

Chronic alcohol ingestion appears to increase susceptibility of the pancreas to pancreatitis through multiple mechanisms. The aim of the current study was to determine the effect of chronic low- and high-dose alcohol consumption on the neurohormonal control of the exocrine pancreas in rats. Male Wistar rats were fed Lieber DeCarli liquid control-, low-, and high-dose alcohol diets for 3 months. Pancreatic exocrine secretion was measured under basal and 2-deoxy-D-glucose (2-DG)-, CCK-, bethanechol-, or meal-stimulated conditions while on chronic alcohol diets and after 2-DG or CCK stimulation during alcohol withdrawal in awake rats. Chronic alcohol ingestion was associated with a dose-related inhibition of basal pancreatic protein secretion, which was reversed upon alcohol withdrawal. Low-dose alcohol feeding had no effect on bethanechol-stimulated pancreatic secretion but altered 2-DG-stimulated pancreatic secretion. In chronic high-dose alcohol rats, meal- and bethanechol-stimulated protein secretion was significantly potentiated during early and late phases. The response to CCK appeared to be disinhibited, whereas the response to 2-DG was uniformly blunted. Upon withdrawal of low-dose alcohol, the response to 2-DG was potentiated, whereas with the withdrawal of high-dose alcohol, the response to CCK was potentiated. Adaptation to chronic alcohol consumption differs depending on the alcohol dose. The most significant effects were seen after high-dose alcohol withdrawal, with apparent loss of central inhibitory regulation combined with exaggerated response at the acinar cell level. This combination of factors could increase susceptibility to acute alcoholic pancreatitis through a hyperstimulation mechanism.