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PubMed1991

Inhibition of ethanol metabolism by fructose in alcohol dehydrogenase-deficient deer mice in vivo.

The purpose of this work was to compare the roles of a newly described mitochondrial dehydrogenase and catalase in ethanol elimination in deer mice deficient in alcohol dehydrogenase (ADH-). Fructose was used because of its well-known ability to stimulate dehydrogenase-dependent ethanol metabolism. Rates of ethanol metabolism in vivo were decreased significantly by about 60% in a dose-dependent manner by fructose in deer mice fed an ethanol-containing or a corn oil control diet. In addition, rates of metabolism of methanol, a selective substrate for catalase in rodents, were similar to rates of ethanol elimination and were decreased from 6.9 +/- 1.0 to 1.7 +/- 0.5 mmol/kg/h by fructose, supporting the hypothesis that catalase and not a mitochondrial dehydrogenase predominates in ethanol oxidation in ADH-deer mice. Glycolate, a substrate for peroxisomal H2O2 generation, reversed the inhibition of alcohol metabolism by fructose completely, indicating that fructose did not inhibit catalase directly. As expected, the ATP/ADP ratio was decreased by fructose significantly from 4.2 +/- 0.4 to 2.4 +/- 0.4 in deer mouse livers. These data are consistent with the hypothesis that fructose decreases catalase-dependent ethanol metabolism in vivo by inhibiting hepatic H2O2 generation.

Adenine Nucleotides↗
PubMed1992

Retinol forms retinoic acid via retinal.

Hepatic cytosol from normal deermice having cytosolic alcohol dehydrogenase (ADH+) also displays retinol dehydrogenase activity and converts retinol to retinoic acid, whereas cytosol from ADH- deermice lacks these enzyme activities and does not produce retinoic acid. Furthermore, microsomes from either strain do not convert retinol to retinoic acid. However, when cytosol from ADH- animals is added to the microsomes, retinoic acid is produced. The obligatory role of retinal as an intermediary step in retinoic acid formation is further shown by isotopic dilution of retinoic acid formed from labeled retinol upon addition of unlabeled retinal. Microsomal retinol dehydrogenase also catalyzes the reduction of retinal to retinol, thereby explaining the decrease in retinoic acid production from retinol in liver cytosol of ADH+ deermice when microsomes are added. Thus, the results of this study indicate that retinal is an obligatory intermediate in the hepatic production of retinoic acid from retinol and that cytosolic and microsomal retinol dehydrogenases play a key role in this process.

Alcohol Dehydrogenase↗
PubMed1985

Bile acids in deermice lacking liver alcohol dehydrogenase.

Liver alcohol dehydrogenase (EC 1.1.1.1) is believed to catalyze the oxidation of 26-hydroxylated intermediates in the biosynthesis of bile acids from cholesterol. We have therefore analyzed the composition and size of the bile acid pool in deer-mice genetically lacking alcohol dehydrogenase. Cholic acid was found to be the major primary bile acid accompanied by small amounts of chenodeoxycholic acid. Variable amounts of secondary bile acids were also present, mainly deoxycholic acid and 3 alpha, 12 alpha-dihydroxy-7-oxo-5 beta-cholanoic acid. The same bile acids were found in animals with normal levels of alcohol dehydrogenase. The pool of bile acids in the gallbladder, small intestine and large intestine varied between 4.2 and 8.4 mumol in four animals lacking alcohol dehydrogenase and between 6.0 and 8.4 mumol in four control animals. Ethanol did not influence pool size or composition of bile acids in the animal studied. It is concluded that alcohol dehydrogenase is not obligatory for normal bile acid biosynthesis.

Alcohol Dehydrogenase↗
PubMed1985

Fatty acid-dependent ethanol metabolism.

Rates of ethanol oxidation by perfused livers from fasted female rats were decreased from 82 +/- 8 to 11 +/- 7 mumol/g/hr by 4-methylpyrazole, an inhibitor of alcohol dehydrogenase. The subsequent addition of fatty acids of various chain lengths in the presence of 4-methylpyrazole increased rates of ethanol uptake markedly. Palmitate (1 mM) increased rates of ethanol oxidation to 95 +/- 8 mumol/g/hr, while octanoate and oleate increased rates to 58 +/- 11 and 68 +/- 15 mumol/g/hr, respectively. Hexanoate, a short-chain fatty acid oxidized predominantly in the mitochondria, had no effect. Addition of oleate also increased the steady-state level of catalase-H2O2. Pretreatment of rats for 1.5 hours with 3-amino-1,2,4-triazole (1.0 g/kg), an inhibitor of catalase, prevented the ethanol-dependent decrease in the steady-state level of catalase-H2O2 completely. Under these conditions, aminotriazole decreased rates of ethanol oxidation by about 50% and blocked the stimulation of ethanol oxidation by fatty acids. Oleate decreased rates of aniline hydroxylation by about 50%, indicating that cytochrome P450 is not involved in the stimulation of ethanol uptake by fatty acids. Furthermore, oleate stimulated ethanol uptake in livers from ADH-negative deermice indicating that fatty acids do not simply displace 4-methylpyrazole from alcohol dehydrogenase. It is concluded that the stimulation of ethanol oxidation by fatty acids is due to increased H2O2 supplied by the peroxisomal beta-oxidation of fatty acids for the catalase-H2O2 peroxidation pathway.

Alcohol Dehydrogenase↗
PubMed1989

Role of peroxisomal fatty acid beta-oxidation in ethanol metabolism.

The contribution of peroxisomal fatty acid beta-oxidation to ethanol metabolism was examined in deermice hepatocytes. Addition of 1 mM oleate to hepatocytes isolated from fasted alcohol dehydrogenase (ADH)-positive deermice in the presence of 4-methylpyrazole or to hepatocytes from fasted or fed ADH-negative deermice produced only a slight and statistically not significant increase in ethanol oxidation. Lactate (10 mM), which is not a peroxisomal substrate, showed a greater effect on ethanol oxidation. There was also a lack of oleate effect on the oxidation of ethanol by hepatocytes of ADH-positive deermice. Furthermore, in ADH-negative deermice, the catalase inhibitor azide (0.1 mM) did not inhibit the increase in ethanol oxidation by oleate and lactate. The rate of oleate oxidation by hepatocytes from fasted ADH-negative deermice was much lower than that of ethanol. These results indicate that in deermice hepatocytes, peroxisomal fatty acid oxidation does not play major role in ethanol metabolism.

Alcohol Dehydrogenase↗
PubMed1984

Ethanol metabolism in vivo by the microsomal ethanol-oxidizing system in deermice lacking alcohol dehydrogenase (ADH).

To assess the importance of non-ADH ethanol metabolism, ADH-negative and ADH-positive deermice were fed liquid diets containing ethanol or isocaloric carbohydrate for 2-4 weeks. Blood ethanol disappearance rate increased significantly after chronic ethanol feeding in both strains. Although at low ethanol concentrations (between 5 and 10 mM) there was no significant difference between ethanol-fed and pair-fed control animals, at high ethanol concentrations (between 40 and 70 mM) blood ethanol elimination rates were increased significantly after chronic ethanol feeding in both ADH-positive and ADH-negative animals. There was no significant effect of the catalase inhibitor 3-amino-1,2,4-triazole on the ethanol elimination/rates in both strains. Whereas catalase and ADH activities were not altered after chronic ethanol treatment, the activity of the microsomal ethanol-oxidizing system (MEOS) was enhanced three to four times in both strains, and microsomal cytochrome P-450 content was also increased significantly. When MEOS activity was expressed per cytochrome P-450 content, it was higher in ADH-negative than in ADH-positive animals, and it increased after ethanol administration. When microsomal proteins were separated by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, ethanol-fed animals had a distinct band which reflected the increase in microsomal cytochrome P-450 content and seemed to reflect a unique form of cytochrome P-450 induced by ethanol. Thus, despite the absence of the ADH pathway, a large amount of ethanol was metabolized by MEOS in ADH-negative deermice; this was associated with increased blood ethanol elimination rates, enhanced MEOS activity, and quantitative and qualitative changes of cytochrome P-450.

Alcohol Dehydrogenase↗
PubMed1986

Interaction between ethanol metabolism and mixed-function oxidation in alcohol dehydrogenase positive and negative deermice.

To assess the effect of non alcohol dehydrogenase (ADH) ethanol metabolism on mixed-function oxidation, aminopyrine demethylation was studied in vivo and in vitro in deermice having normal liver ADH (ADH+) or lacking it (ADH-), in the presence and absence of ethanol. When injected 15 min prior to administration of [14C]aminopyrine, ethanol reduced the 14CO2 exhalation rate in both ADH- and ADH+ deermice. The inhibitory effect of ethanol was dose dependent in both strains, and there was no significant difference between strains. Chronic ethanol feeding increased 14CO2 production from [14C]aminopyrine in both animal strains (ADH- alcohol 5.9 +/- 1.3 vs ADH- control 2.9 +/- 0.03, P less than 0.025; ADH+ alcohol 5.9 +/- 0.3 vs ADH+ control 2.7 +/- 1.3 nmoles aminopyrine/100 g body wt/min, P less than 0.001). Alcohol feeding also induced aminopyrine N-demethylase activity measured in vitro. This induction was more pronounced in ADH- deermice. Ethanol also inhibited aminopyrine demethylation in liver homogenates from ADH- and ADH+ animals in a dose-dependent manner and to a comparable degree in both strains. The kinetics of aminopyrine N-demethylase inhibition by ethanol was competitive in the microsomal fraction from ADH- as well as ADH+ animals. These results suggest that inhibition of mixed-function oxidation by ethanol may be due to an effect of ethanol on the hepatic microsomes rather than to redox changes produced by ADH-mediated ethanol oxidation. Further, chronic ethanol feeding increased microsomal aminopyrine demethylation independently of the presence of ADH.

Alcohol Dehydrogenase↗
PubMed1986

Assessment of the role of non-ADH ethanol oxidation in vivo and in hepatocytes from deermice.

Deermice genetically lacking alcohol dehydrogenase (ADH-) were used to quantitate the effect of 4-methylpyrazole (4-MP) on non-ADH pathways in hepatocytes and in vivo. Although primarily an inhibitor of ADH, 4-methylpyrazole was also found to inhibit competitively the activity of the microsomal ethanol-oxidizing system (MEOS) in deermouse liver microsomes. The degree of 4-MP inhibition in ADH- deermice then served to correct for the effect of 4-MP on non-ADH pathways in deermice having ADH (ADH+). In ADH+ hepatocytes, the percent contributions of non-ADH pathways were calculated to be 28% at 10 mM and 52% at 50 mM ethanol. When a similar correction was applied to in vivo ethanol clearance rates in ADH+ deermice, non-ADH pathways were found to contribute 42% below 10 mM and 63% at 40-70 mM blood ethanol. The catalase inhibitor 3-amino-1,2,4-triazole, while reducing catalase-mediated peroxidation of ethanol by 83-94%, had only a slight effect on blood ethanol clearance at ethanol concentrations below 10 mM, and no effect at all at 40-70 mM ethanol. These results indicate that non-ADH pathways (primarily MEOS) play a significant role in ethanol oxidation in vivo and in hepatocytes in vitro.

Alcohol Dehydrogenase↗
PubMed1986

Catalase-dependent ethanol metabolism in vivo in deermice lacking alcohol dehydrogenase.

Pathways of ethanol elimination in alcohol dehydrogenase (ADH)-positive and -negative deermice were studied using the catalase inhibitor, 3-amino-1,2,4-triazole. To verify that aminotriazole inhibited catalase effectively, the characteristic decrease in catalase-H2O2 which occurs in saline-treated controls when ethanol is peroxidized was monitored at 660-640 nm in perfused deermouse livers. Following 1.5 hr of pretreatment with aminotriazole (1.5 g/kg), the peroxidatic activity of catalase measured in vitro was inhibited by greater than 99%. Under these conditions, ethanol did not decrease catalase-H2O2 in perfused livers, indicating that catalase was inhibited. Ethanol and aniline oxidation by microsomes were also inhibited by about 67-90% after 1.5 hr of pretreatment with aminotriazole. In ADH-positive deermice, pretreatment with aminotriazole for 1.5 hr prior to injection of ethanol (2.0 g/kg) decreased rates of ethanol elimination in vivo from 13.2 +/- 0.8 to 10.2 +/- 0.4 mmoles/kg/hr. In ADH-negative deermice, similar treatment decreased rates of ethanol elimination in vivo from 4.5 +/- 0.4 to 1.1 +/- 0.6 mmoles/kg/hr. Following pretreatment with aminotriazole (1.0 g/kg) for 6 hr, rates of ethanol elimination in ADH-negative deermice returned to near basal values. Under these conditions, the peroxidatic activity of catalase measured in vitro and the ethanol-dependent decrease in catalase-H2O2 in perfused livers also returned to near basal levels; however, the oxidation of ethanol by cytochrome P-450 was inhibited completely. It is concluded, therefore, that time of pretreatment with aminotriazole is an important variable which must be controlled carefully to inhibit catalase completely. Since catalase was active while cytochrome P-450 was not following 6 hr of pretreatment with aminotriazole, it is concluded that ethanol elimination occurs predominantly via catalase-H2O2 in ADH-negative deermice under these conditions.

Alcohol Dehydrogenase↗
PubMed1992

Multiple retinoid dehydrogenases in testes cytosol from alcohol dehydrogenase negative or positive deermice.

Retinoic acid syntheses from retinol by cytosol from testes of alcohol dehydrogenase negative or positive deermice were similar in specific activity and in their insensitivity to 1 M ethanol or 100 mM 4-methylpyrazole. Anion-exchange followed by size-exclusion chromatography revealed multiple and similarly migrating peaks in each cytosol that had both retinol and retinal dehydrogenase activities. Thus, the effects of ethanol on testes cannot be caused by direct inhibition of cytosolic retinoic acid synthesis because retinoid dehydrogenases distinct from mouse class A2 alcohol dehydrogenases, which corresponds to human class I, occurred in testes and they were not inhibited by ethanol. These data also demonstrate the occurrence of multiple cytosolic retinoic acid synthesis activities and indicate that the two reactions of cytosolic retinoic acid synthesis, retinol and retinal dehydrogenation, may be catalyzed by enzymes that occur as complexes.

Alcohol Dehydrogenase↗
PubMed1994

Antagonistic effects of the selective, competitive N-methyl-D-aspartate (NMDA) receptor antagonist, NPC 12626, on kappa opiate-induced analgesia in male deer mice.

The present study examined the effects of the competitive NMDA antagonist, NPC 12626, on the analgesic effects of the specific kappa opiate receptor agonist, U69,593, in male deer mice. Intraperitoneal (i.p.) administration of NPC 12626 had no effect on the basal nociceptive sensitivity of reproductive male deer mice, as measured by latency of response to a thermal (50 degrees C) surface. NPC 12626 dose-dependently (0.05-1.0 mg/kg) reduced U69,593-induced analgesia. NPC 12626 at 1.0 mg/kg attenuated U69,593-induced analgesia in a manner comparable to that produced by the specific kappa opiate antagonist, nor-binaltorphimine. In contrast, this dose of NPC 12626 potentiated the analgesia produced by the predominantly mu agonist morphine (1.0 mg/kg). The non-competitive NMDA antagonist, MK-801, which has been previously indicated to affect kappa opiate analgesia, significantly reduced at 1.0 mg/kg, but did not block, the analgesia produced by U69,593 and in contrast to NPC 12626, slightly reduced morphine-induced analgesia. These findings suggest that the NMDA antagonist, NPC 12626, may, either directly or indirectly, have effects on kappa opiate receptor mediated mechanisms.

Amino Acids↗
PubMed1985

Organizational and activational effects of sex steroids on brain and behavior: a reanalysis.

The actions of sex steroids on brain and behavior traditionally have been divided into organizational and activational effects. Organizational effects are permanent and occur early in development; activational effects are transient and occur throughout life. Over the past decade, experimental results have accumulated which do not fit such a simple two-process theory. Specifically, the characteristics said to distinguish organizational and activational effects on behavior are sometimes mixed, as when permanent effects occur in adulthood. Attempts to determine whether specific cellular processes are uniquely associated with either organizational or activational effects are unsuccessful. These considerations blur the organizational-activational distinction sufficiently to suggest that a rigid dichotomy is no longer tenable.

Animals↗