Ulrich A. Simanowski

Serum collagen type VI and XIV and hyaluronic acid as early indicators for altered connective tissue turnover in alcoholic liver disease.

Hepatic fibrosis in alcoholic liver disease often heralds progression to cirrhosis and, therefore, noninvasive parameters are required for early diagnosis and follow-up. Collagens VI and XIV, procollagen-III-N-propeptide, hyaluronic acid, and active transforming growth factor-β1 (TGF-β1) were measured in healthy volunteers, patients with alcoholic cirrhosis, and heavy drinkers without cirrhosis. Noncirrhotic alcoholics were assigned to two groups with either normal aspartate aminotransferase or levels ≥2 normal. Collagens VI and XIV were elevated in all alcoholic patients compared to controls (P < 0.0001, all instances). Procollagen-III-N-propeptide and hyaluronic acid levels were higher in alcoholic patients with elevated liver enzymes and in cirrhotics as compared to controls. Procollagen-III-N-propeptide revealed a significant correlation with serum levels of TGF-β1(P < 0.0001). Collagens VI, and XIV, procollagen-III-N-propeptide, and hyaluronic acid appear to be sensitive markers indicating fibrotic transformation in alcoholics. The correlation between procollagen-III-N-propeptide and TGF-β1 emphasizes its role in hepatic fibrogenesis.

Alcohol dehydrogenase in the human colon and rectum.

Alcohol dehydrogenase (ADH) activities were measured in rectal biopsies from 55 patients (28 males, 27 females aged 22-81 years), in colonic biopsies from 19 patients (10 males, 9 females aged 21-81 years) and in three surgical specimens. All patients had normal mucosa as determined by light microscopy. The activity of rectal ADH was comparable to gastric ADH activity and did not exhibit any significant gender effect (5.5 +/- 1.1 vs. 6.7 +/- 1.0 nmol/mg protein x min; nonsignificant). No significant correlation was found between age and rectal ADH activity. Compared to ADH activities in other colonic segments, rectal ADH activity was found to be significantly increased (ascending colon: 3.9 +/- 0.7 nmol/mg protein x min; p < 0.05; transversal colon: 3.4 +/- 1.1 nmol/mg protein x min; p < 0.05; descending colon 2.3 +/- 0.4 nmol/mg protein x min; p < 0.001; rectum 6.1 +/- 0.8 nmol/mg protein x min). This higher activity of ADH in the rectum could result in increased acetaldehyde levels after alcohol administration and could therefore play a role, at least in part, in the ethanol-associated rectal cocarcinogenesis.

Effect of aging on in vivo and in vitro ethanol metabolism and its toxicity in F344 rats

To investigate the effect of aging on ethanol metabolism, 24 male and female F344 rats aged 2 and 12 mo that were fed a laboratory diet received ethanol (1.2 and 2.5 g/kg body wt) intraperitoneally. In male rats, in vivo ethanol elimination significantly decreased according to age both at high (436 +/- 38 vs. 294 +/- 27 mg/kg.h; p less than 0.01) and low (365 +/- 19 vs. 261 +/- 8 mg/kg.h; p less than 0.01) blood ethanol concentrations. Age did not influence the specific activity of hepatic or gastric alcohol dehydrogenase, whereas the activity was significantly decreased with age in the liver (p less than 0.05) and in the stomach (p less than 0.001) when related to body weight. In addition, the activity of the hepatic microsomal ethanol oxidizing system decreased significantly according to age (8.7 +/- 0.5 vs. 6.00 +/- 0.3 nmol/min.mg micr. protein; p less than 0.001). To study the response of ethanol-metabolizing enzymes to chronic ethanol ingestion, 2- and 19-mo-old male F344 rats were pair-fed nutritionally adequate liquid diets containing 36% of total calories either as ethanol or isocaloric carbohydrate for 3 wk. In this experiment specific alcohol dehydrogenase activity was not significantly affected by age, whereas the hepatic microsomal function estimated by the determination of cytochrome P450, microsomal ethanol oxidizing system, and aniline hydroxylation as well as hepatic mitochondrial low Km-acetaldehyde dehydrogenase activity was found to be markedly depressed with age (p less than 0.01). Chronic ethanol consumption increased microsomal enzyme activities in older rats to levels comparable to those observed in young animals prior to ethanol administration. Chronic ethanol feeding also resulted in an increased hepatic fat accumulation, which was significantly enhanced in older rats. In contrast to male rats, in vivo ethanol metabolism was practically identical for 2- and 12-mo-old female rats. These data demonstrate an enhanced toxicity of alcohol in older compared to younger male but not female rats associated with a delay in alcohol elimination both at high and low ethanol blood concentrations and a decrease in ethanol- and acetaldehyde-metabolizing enzyme activities.

Effect of age and gender on in vivo ethanol elimination, hepatic alcohol dehydrogenase activity, and NAD+ availability in F344 rats

SummaryIt has been reported that aging strikingly decreases in vivo ethanol metabolism in F344 rats without major effects on hepatic alcohol dehydrogenase (ADH) activity. Because hepatic ADH activity is not always rate limiting in the oxidation of ethanol, we measured in vivo ethanol elimination rate (EER), hepatic ADH activity, and the hepatic-cytoplasmic and mitochondrial redox states after acute ethanol application in 2- and 12-month-old F344 rats of both sexes. In male, but not in female, animals EER decreased with age significantly, by 28% (P<0.01). The body-to-liver weight ratio was significantly increased in male (39.4±1.5 vs 46.5±2.0;P<0.05), but not in female, animals with age. Specific activity of ADH was not significantly changed by age, while the activity was significantly reduced with age in male, but not female, rats when related to body weight (5.1±0.4 vs 3.9±0.3 μmoles/100 g b.wt./min;P<0.05). The cytoplasmic, but not the mitochondrial (NAD+) to (NADH), ratio was significantly decreased with age in male livers (317±48 vs 793±128,P<0.05), while this was not the case in female livers. In summary, the data show a sex dependence of the effect of age on ethanol metabolism. The observed reduction in in vivo EER with age in male animals is due at least in part to an increased body-to-liver weight ratio, decreased hepatic ADH activity, and reduced availability of NAD+, the cofactor of the ADH reaction. The cause of this may be decreased transport of reducing equivalents through the mitochondrial membrane due to a lack of shuttle systems or a change in the physicochemical properties of the mitochondrial membrane, or decreased reutilization of NADH as NADPH resulting from a reduction of microsomal ethanol oxidation with age.

Helicobacter pylori infection decreases gastric alcohol dehydrogenase activity and first-pass metabolism of ethanol in man.

Background/Aims: Ethanol is metabolized by alcohol dehydrogenase in the human stomach. This metabolism contributes to the so-called first-pass metabolism of ethanol which is affected by gender, medication, and morphological alterations of the gastric mucosa. Recently, it has been shown that Helicobacter pylori is capable to oxidize ethanol to acetaldehyde in vitro. Since H. pylori also injures gastric mucosa, the present study examines the effect of this bacterium on gastric alcohol dehydrogenase activity and systemic availability of ethanol in vivo. Methods: Thirteen volunteers (7 men and 6 women, aged 18–52 years) with gastric H. pylori infection diagnosed by a positive CLO test and positive gastric histology received ethanol (0.225 g/kg) either orally or intravenously before and after H. pylori elimination to determine systemic availability of ethanol. In addition, gastric biopsy specimens were taken from all subjects before and after H. pylori elimination for histological assessment of mucosal alterations and determinations of gastric alcohol dehydrogenase activity and phenotype of the enzyme. Results: In the presence of H. pylori the first-pass metabolism of ethanol was found to be significantly reduced (625 ± 234 vs. 1,155 ± 114 mg/dl/min, p = 0.046). This reduction of first-pass metabolism of ethanol was associated with a significant decrease in alcohol dehydrogenase activity (4.8 ± 1.5 vs. 12.1 ± 2.3 nmol/mg protein × min, p < 0.05) and an increase in the severity of mucosal damage as determined by a histological score (p < 0.05). Conclusions: H. pylori infection leads to gastric mucosal injury which is associated with a decrease in gastric alcohol dehydrogenase activity and first-pass metabolism of ethanol. Ethanol metabolism by H. pylori does not play an important role in vivo. However, gastric morphology is one important factor determining systemic availability of ethanol in man.