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Biomedical subjects

D T Forman

Publications and source records attributed to D T Forman.

At least 19 recordsLinked to original sources
PubMed2000

Estrogen is involved in early alcohol-induced liver injury in a rat enteral feeding model.

The aim of this study was to investigate whether reduction in blood estrogen by removal of the ovaries would decrease the sensitivity of female rats to early alcohol-induced liver injury using an enteral ethanol feeding model, and if so, whether estrogen replacement would compensate. Livers from ovariectomized rats with or without estrogen replacement after 4 weeks of continuous ethanol exposure were compared with nonovariectomized rats in the presence or absence of ethanol. Ethanol increased serum alanine transaminase (ALT) levels from 30 +/- 6 to 64 +/- 7 U/L. This effect was blocked by ovariectomy (31 +/- 7) and totally reversed by estrogen replacement (110 +/- 23). Ethanol increased liver weight and fat accumulation, an effect that was minimized by ovariectomy and reversed partially by estrogen replacement. Infiltrating leukocytes were increased 6. 7-fold by ethanol, an effect that was blunted significantly by ovariectomy and reversed by estrogen replacement. Likewise, a similar pattern of changes was observed in the number of necrotic hepatocytes. Blood endotoxin and hepatic levels of CD14 messenger RNA (mRNA) and protein were increased by ethanol. This effect was blocked in ovariectomized rats and elevated by estrogen replacement. Moreover, Kupffer cells isolated from ethanol-treated rats with estrogen replacement produced more tumor necrosis factor alpha (TNF-alpha) than those from control and ovariectomized rats. It is concluded, therefore, that the sensitivity of rat liver to alcohol-induced injury is directly related to estrogen, which increases endotoxin in the blood and CD14 expression in the liver, leading to increased TNF-alpha production.

Alanine Transaminase↗
PubMed2000

Gender differences in early alcohol-induced liver injury: role of CD14, NF-kappaB, and TNF-alpha.

The purpose of this study was to determine whether early alcohol-induced liver injury (ALI) in females is associated with changes in CD14 on Kupffer cells, activation of hepatic nuclear factor (NF)-kappaB, and expression of tumor necrosis factor (TNF)-alpha mRNA. Male and female rats were given high-fat control or ethanol-containing diets for 4 wk using the intragastric enteral protocol. Physiological parameters were similar in both genders. Ethanol was increased as tolerance developed with higher blood levels than previously observed, resulting in a fourfold increase in aspartate aminotransferase (males 389 +/- 47 IU/l vs. females 727 +/- 66 IU/l). Hepatic pathology developed more rapidly and was nearly twofold greater and endotoxin levels were significantly higher in females after ethanol. Also, expression of CD14 on Kupffer cells was 1.5-fold greater and binding of transcription factor NF-kappaB in hepatic nuclear extracts and TNF-alpha mRNA expression were threefold greater in females. These data are consistent with the hypothesis that elevated endotoxin after ethanol triggers more activation of Kupffer cells via enhanced CD14 expression in females. NF-kappaB is activated in this process, leading to increases in TNF-alpha mRNA expression in the liver and more severe liver injury in females. It is concluded that gender differences in ALI are dependent on endotoxin and a signaling cascade leading to TNF-alpha.

Animals↗
PubMed1999

Mechanisms of alcohol-induced hepatotoxicity: studies in rats.

Alcohol treatment results in increases in the release of endotoxin from gut bacteria and membrane permeability of the gut to endotoxin, or both. Females are more sensitive to these changes. Elevated levels of endotoxin activate Kupffer cells to release substances such as eicosanoids, TNF-alpha and free radicals. Prostaglandins increase oxygen uptake and most likely are responsible for the hypermetabolic state in the liver. The increase in oxygen demand leads to hypoxia in the liver, and on reperfusion, alpha-hydroxyethyl free radicals are formed which lead to tissue damage in oxygen-poor pericentral regions of the liver lobule.

Animals↗
PubMed1999

Amino acids in rinse effluents as a predictor of graft function after transplantation of fatty livers in rats.

There are too few reliable markers by which one can predict future function of a liver before implantation. Consequently, the purpose of this study was to test the hypothesis that amino acids in rinse-effluents could predict transplant outcome in marginal fatty livers from rats. Amino acids were measured in the rinse effluent from the livers immediately after harvest and graft preparation or cold storage. Amino acids in the effluent were twice as high in ethanol-treated animals compared to those in nonfatty controls. Ethanol-treated fatty livers survived for no longer than 7 days after transplantation while 83% of nonfatty controls survived (P < 0.05). In subsequent studies, the cold-storage time was decreased to 6 h to determine whether failing fatty livers released more amino acid than grafts that would function normally. There was a significant increase in amino acids in the effluent of fatty grafts compared to controls. Moreover, the sum of the four selected amino acids (alanine, valine, histidine, leucine) was lower than 23 nmol/g liver in functional livers, whereas failing grafts had totals significantly higher than 25 nmol/g liver. The sum of the four amino acids correlated well with 24 h post-transplant serum AST levels (r = 0.78, P < 0.0001). So we can conclude that amino acid release can serve as a useful marker of graft viability and reliably predicts survival.

Alanine Transaminase↗
PubMed1999

Dietary glycine and renal denervation prevents cyclosporin A-induced hydroxyl radical production in rat kidney.

Cyclosporin A (CsA) nephrotoxicity is associated with renal hypoxia and increases in free radicals in the urine. This study was designed to elucidate the mechanism of radical production caused by CsA. Pretreatment of rats with CsA (25 mg/kg, i.g.) for 5 days decreased glomerular filtration rates by 65%, an effect largely prevented by both dietary glycine (5%) or renal denervation. CsA dissolved in olive oil produced a 6-line alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (4-POBN)/free radical signal in the urine, which partitioned predominantly into the aqueous phase after chloroform extraction (i.e., it is water soluble). Dimethyl sulfoxide (DMSO) is attacked by the hydroxyl radical to produce a methyl radical; administration of CsA with [(12)C]DMSO produced two radical species in urine, one with hyperfine coupling constants similar to the 4-POBN/methyl radical adduct found in aqueous solution. CsA given with [(13)C]DMSO produced a 12-line spectrum, confirming the formation of hydroxyl radicals. The methyl radical produced by the hydroxyl radical represented 62% of radicals detected in urine but only 15% in bile. Therefore, hydroxyl radicals are produced largely in the kidney. Free radicals in urine were increased about 5-fold by CsA, an effect completely blocked by the inhibitory neurotransmitter, glycine, or by renal denervation. CsA infusion for 30 min increased efferent renal nerve activity 2-fold, and dietary glycine (5%) totally blocked this phenomenon. Taken together, these data are consistent with the hypothesis that CsA increases hydroxyl radical formation by increasing renal nerve activity resulting in vasoconstriction and hypoxia-reoxygenation. Glycine blunts the effect of CsA on the renal nerve, which explains, in part, prevention of nephrotoxicity.

Animals↗
PubMed1999

Peroxisomes are involved in the swift increase in alcohol metabolism.

The purpose of this study was to determine whether catalase-dependent alcohol metabolism is activated by alcohol (i.e., swift increase in alcohol metabolism). When ethanol or the selective substrate for catalase, methanol, was given (5.0 g/kg) in vivo 2 to 3 h before liver perfusion, methanol and oxygen metabolism were increased significantly. This increase was blocked when the specific Kupffer cell toxicant GdCl3 was administered 24 h before perfusion. These data support the hypothesis that catalase-dependent alcohol metabolism is activated by acute alcohol and that Kupffer cells are involved. Ethanol treatment in vivo increased ketogenesis from endogenous fatty acids nearly 3-fold and increased plasma triglycerides and hepatic acyl CoA synthetase activity; all increases were blocked by GdCl3. These findings support the hypothesis that ethanol increases H2O2 supply for catalase-dependent alcohol metabolism by increasing fatty acid supply. Infusion of oleate stimulated oxygen uptake 1.5-fold and methanol metabolism 4-fold, but these parameters were not altered by GdCl3. Moreover, the effects of ethanol treatment were blocked by the cyclooxygenase inhibitor indomethacin, and prostaglandin E2 (PGE2) was increased more than 200% in media from cultured Kupffer cells from rats treated with ethanol in vivo. Furthermore, lipoprotein lipase activity in retroperitoneal fat pads, which is known to be inhibited by PGE2, was reduced 70% by ethanol. These data are consistent with the hypothesis that Kupffer cells play a key role in activation of catalase-dependent alcohol metabolism, most likely by producing mediators (e.g., PGE2) that inhibit lipoprotein lipase, increase the supply of fatty acids to the liver, and increase generation of H2O2 via peroxisomal beta-oxidation.

Animals↗
PubMed1998

Estrogen increases sensitivity of hepatic Kupffer cells to endotoxin.

The relationship among gender, lipopolysaccharide (LPS), and liver disease is complex. Accordingly, the effect of estrogen on activation of Kupffer cells by endotoxin was studied. All rats given estrogen intraperitoneally 24 h before an injection of a sublethal dose of LPS (5 mg/kg) died within 24 h, whereas none of the control rats died. Mortality was prevented totally by pretreatment with gadolinium chloride, a Kupffer cell toxicant. Peak serum tumor necrosis factor-alpha (TNF-alpha) values as well as TNF-alpha mRNA in the liver after LPS were twice as high in the estrogen-treated group as in the untreated controls. Plasma nitrite levels and inducible nitric oxide synthase in the liver were also elevated significantly in estrogen-treated rats 6 h after LPS. Furthermore, Kupffer cells isolated from estrogen-treated rats produced about twice as much TNF-alpha and nitrite as controls did in response to LPS. In addition, Kupffer cells from estrogen-treated rats required 15-fold lower amounts of LPS to increase intracellular Ca2+ than controls did, and Kupffer cells from estrogen-treated animals expressed more CD14, the receptor for LPS/LPS binding protein, than controls. Moreover, estrogen treatment increased LPS binding protein mRNA dramatically in liver in 6-24 h. It is concluded that estrogen treatment in vivo sensitizes Kupffer cells to LPS, leading to increased toxic mediator production by the liver.

Acute-Phase Proteins↗
PubMed1998

The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury.

Previous research from this laboratory using a continuous enteral ethanol (EtOH) administration model demonstrated that Kupffer cells are pivotal in the development of EtOH-induced liver injury. When Kupffer cells were destroyed using gadolinium chloride (GdCl3) or the gut was sterilized with polymyxin B and neomycin, early inflammation due to EtOH was blocked. Anti-tumour necrosis factor (TNF)-alpha antibody markedly decreased EtOH-induced liver injury and increased TNF-mRNA. These findings led to the hypothesis that EtOH-induced liver injury involves increases in circulating endotoxin leading to activation of Kupffer cells. Pimonidazole, a nitro-imidazole marker, was used to detect hypoxia in downstream pericentral regions of the lobule. Following one large dose of EtOH or chronic enteral EtOH for 1 month, pimonidazole binding was increased significantly in pericentral regions of the liver lobule, which was diminished with GdCl3. Enteral EtOH increased free radical generation detected with electron spin resonance (ESR). These radical species had coupling constants matching alpha-hydroxyethyl radical and were shown conclusively to arise from EtOH based on a doubling of the ESR lines when 13C-EtOH was given. Alpha-hydroxyethyl radical production was also blocked by the destruction of Kupffer cells with GdCl3. It is known that females develop more severe EtOH-induced liver injury more rapidly and with less EtOH than males. Female rats on the enteral protocol exhibited more rapid injury and more widespread fatty changes over a larger portion of the liver lobule than males. Plasma endotoxin, ICAM-1, free radical adducts, infiltrating neutrophils and transcription factor NFkappaB were approximately two-fold greater in livers from females than males after 4 weeks of enteral EtOH treatment. Furthermore, oestrogen treatment increased the sensitivity of Kupffer cells to endotoxin. These data are consistent with the hypothesis that Kupffer cells participate in important gender differences in liver injury caused by ethanol.

Animals↗
PubMed1997

Role of Kupffer cells, endotoxin and free radicals in hepatotoxicity due to prolonged alcohol consumption: studies in female and male rats.

Alcohol ingestion results in increases in the release of endotoxin from gut bacteria or membrane permeability of the gut to endotoxin, or both. Female rats are more sensitive to these changes. Elevated levels of endotoxin activate Kupffer cells to release substances such as eicosanoids, tumor necrosis factor-alpha and free radicals. Prostaglandins increase oxygen uptake and most likely are responsible for the hypermetabolic state in the liver. The increase in oxygen demand leads to hypoxia in the liver, and on reperfusion, alpha-hydroxyethyl free radicals are formed that lead to tissue damage in oxygen-poor pericentral regions of the liver lobule.

Animals↗
PubMed1996

Glycine prevents alcohol-induced liver injury by decreasing alcohol in the rat stomach.

BACKGROUND & AIMS: Inactivation of Kupffer cells prevents alcohol-induced liver injury, and hypoxia subsequent to a hypermetabolic state caused by activated Kupffer cells probably is involved in the mechanism. Glycine is known to prevent hepatic reperfusion injury. The purpose of this study was to determine whether glycine prevents alcohol-induced liver injury in vivo. METHODS: Male Wistar rats were exposed to ethanol (10-12 g.kg-1.day-1) continuously for up to 4 weeks via an intragastric feeding protocol. The effect of glycine on the first-pass metabolism of ethanol was also examined in vivo, and the effect on alcohol metabolism was estimated specifically in perfused liver. RESULTS: Glycine decreased ethanol concentrations precipitously in urine, breath, peripheral blood, portal blood, feces, and stomach contents. Serum aspartate amino-transferase levels were elevated to 183 U/L after 4 weeks of ethanol-treatment. In contrast, values were significantly lower in rats given glycine along with ethanol. Hepatic steatosis and necrosis also were reduced significantly by glycine. Glycine dramatically increased the first-pass elimination of ethanol in vivo but had no effect on alcohol metabolism in the perfused liver. CONCLUSIONS: Glycine minimizes alcohol-induced liver injury in vivo by preventing ethanol from reaching the liver by activating first-pass metabolism in the stomach.

Analysis of Variance↗
PubMed1996

A diet containing glycine improves survival in endotoxin shock in the rat.

In this study, we investigated the effects of a glycine-containing diet (5%) on mortality and liver injury due to intravenous injection of endotoxin [Escherichia coli lipopolysaccharide (LPS)] in Sprague-Dawley rats in vivo. Fifty percent of the rats fed control diet died within 24 h after an intravenous injection of LPS (10 mg/kg), whereas feeding the rats glycine totally prevented mortality and markedly reduced an LPS-induced elevation of serum transaminase levels, hepatic necrosis, and lung injury. The elevation in serum tumor necrosis factor-alpha (TNF-alpha) due to LPS was also blunted and delayed significantly by glycine feeding. In a two-hit model (hepatic ischemia-reperfusion and injection of sublethal LPS), all rats fed control diet died, whereas 83% of glycine-fed animals survived with a significant reduction in transaminases and improved liver and lung histology. LPS elevated intracellular Ca2+ concentration ([Ca2+]i) in cultured Kupffer cells, an effect blocked almost completely by glycine. Glycine most likely reduces injury and mortality by preventing the LPS-induced elevation of [Ca2+]i in Kupffer cells, thereby minimizing toxic eicosanoid and cytokine production.

Animal Feed↗
PubMed1993

Evidence that catalase is a major pathway of ethanol oxidation in vivo: dose-response studies in deer mice using methanol as a selective substrate.

Recently, it was demonstrated that 4-methylpyrazole was not only an inhibitor of alcohol dehydrogenase but also caused competitive inhibition of fatty acyl-CoA synthetase, the enzyme which activates fatty acids (B. U. Bradford, D. T. Forman, and R. G. Thurman, 1993, Mol. Pharmacol. 43, 115-119). Rates of catalase-dependent alcohol metabolism were decreased in alcohol dehydrogenase-negative (ADH-) deer mice because the H2O2 supply for catalase via peroxisomal fatty acid oxidation was inhibited due to substrate limitation. In light of these findings it became necessary to reevaluate the role of catalase and alcohol dehydrogenase in alcohol metabolism. In this study, methanol, a selective substrate for catalase in rodents, was compared with ethanol. Rates of ethanol and methanol metabolism were studied in vivo at blood alcohol levels ranging from 50 to 500 mg/dl. In the ADH- deer mouse, rates of methanol and ethanol metabolism increased when alcohol was elevated from 0 to 100 mg/dl and were maximal at values around 6-8 mmol/kg/h (half-maximal rates were observed at blood alcohol levels around 50 mg/dl). In the ADH+ deer mouse, rates of ethanol metabolism increased to values around 9 mmol/kg/h at 100 mg/dl and remained constant at blood levels up to 500 mg/dl. In contrast, rates of methanol metabolism increased to values of only 5 mmol/kg/h at levels of 100 mg/dl (the half-maximal rate was about 2.5 mmol/kg/h at 50 mg/dl) followed by a steady increase to 9 mmol/kg/h as the blood level was increased from 100 to 500 mg/dl (the half-maximal rate for this second component was around 6 mmol/kg/h at 300 mg/dl). Rates of methanol uptake were 50 +/- 4 nmol/min/mg protein in 10,000g pellets from ADH- deer mouse livers; however, methanol was not metabolized by isolated microsomes. The catalase inhibitor aminotriazole decreased ethanol and methanol metabolism 75% in ADH- deer mice. Further, olive oil, which is rich in oleate, increased methanol metabolism from 7 to 11.5 mmol/kg/h. This stimulation was blocked by fructose, which diminishes ATP and decreases H2O2 supply. In the ADH+ deer mouse, fructose (2 g/kg) stimulated ethanol metabolism as expected; however, inhibition of both ethanol and methanol metabolism was observed with higher doses of fructose (10 g/kg). Taken together, these data support the hypothesis that catalase is the predominant pathway for alcohol metabolism in the ADH- deer mouse. The contribution of catalase was about 50% in the ADH+ mutant at low doses of ethanol and approached 100% as the alcohol concentration was elevated.

Alcohol Dehydrogenase↗
PubMed1993

4-Methylpyrazole inhibits fatty acyl coenzyme synthetase and diminishes catalase-dependent alcohol metabolism: has the contribution of alcohol dehydrogenase to alcohol metabolism been previously overestimated?

Alcohol dehydrogenase (ADH)-deficient deer mice were used as an animal model to investigate the effect of 4-methylpyrazole on alcohol metabolism. After intraperitoneal dosing of these mutant mice with 4-methylpyrazole, rates of ethanol and methanol metabolism in vivo were decreased significantly, by 41% and 35%, respectively. In perfused liver, rates of ethanol metabolism were also decreased up to 61% by 100 microM 4-methylpyrazole. Further, when livers were perfused with methanol, a selective substrate for catalase, rates of methanol metabolism were decreased by 64% by 4-methylpyrazole. It was further determined that 4-methylpyrazole administration caused negligible changes in total hepatic catalase activity and in rates of oxidation of ethanol by isolated microsomes; rather, it acts on catalase-dependent alcohol metabolism by limiting the supply of H2O2. In this study, 4-methylpyrazole inhibited fatty acyl CoA synthetase competitively in liver homogenates. Fatty acyl CoA synthetase is a key enzyme involved in the supply of substrate for peroxisomal oxidation of alcohols via catalase-H2O2. When palmitate was studied, rates of formaldehyde production from methanol were reduced competitively by 4-methylpyrazole; however, when the product palmitoyl CoA was used, the addition of 4-methylpyrazole did not alter activity. 4-Methylpyrazole also inhibited fatty acyl CoA synthetase activity measured directly from CoA disappearance. These data indicate that fatty acyl CoA synthetase is inhibited by 4-methylpyrazole, thus reducing the availability of H2O2 for catalase-dependent alcohol metabolism. Inhibition of methanol metabolism in deer mice expressing ADH indicates that this phenomenon also occurs in species with ADH. Taken together, these data support the hypothesis that the contribution of ADH to alcohol metabolism may have been previously overestimated.

Alcohol Dehydrogenase↗
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↗
PubMed1990

Transient hyperglycemia during abdominal aortic surgery.

A 64-year-old man undergoing abdominal aortic aneurysm repair with no history of diabetes mellitus had an episode of marked hyperglycemia during surgery. The peak concentration of glucose in plasma was 43.2 mmol/L. This hyperglycemia responded immediately to administration of 30 units of regular insulin. Factors involved in the hyperglycemia included surgical stress, multiple medications, and the anesthetic used (isoflurane), but do not fully account for the magnitude of the increase in glucose. The data suggest that the patient may have had an underlying insulin deficiency, which was unmasked by the stress of surgery.

Aged↗
PubMed1987

Inhibition of catalase-dependent ethanol metabolism in alcohol dehydrogenase-deficient deermice by fructose.

Hepatic microsomal fractions from ADH (alcohol dehydrogenase)-negative deermice incubated with an NADPH-generating system metabolized butanol and ethanol at rates around 10 nmol/min per mg. In contrast, cytosolic catalase from ADH-negative deermouse liver oxidized ethanol, but not butanol, when incubated with an H2O2-generating system. Thus butanol is oxidized by cytochrome P-450 in microsomal fractions, but not by cytosolic catalase, in tissues from ADH-negative deermice. In perfused livers from ADH-negative deermice, rates of ethanol uptake at low concentrations of ethanol (1.5 mM) were about 60 mumol/h per g, yet butanol (1.5 mM) uptake was undetectable (less than 4 mumol/h per g). At higher concentrations of alcohol (25-30 mM), rates of ethanol uptake were about 80 mumol/h per g, whereas rates of butanol uptake were only about 9 mumol/h per g. Because rates of butanol metabolism via cytochrome P-450 in deermice were more than an order of magnitude lower than rates of ethanol uptake in livers from ADH-negative deermice, it is concluded that ethanol uptake by perfused livers from ADH-negative deermice is catalysed predominantly via catalase-H2O2. In support of this conclusion, rates of H2O2 generation, which are rate-limiting for the peroxidation of ethanol by catalase, were about 65 mumol/h per g in livers from ADH-negative deermice, values similar to rates of ethanol uptake of about 60 mumol/h per g measured under identical conditions. Rates of ethanol uptake by perfused livers from ADH-positive, but not from ADH-negative, deermice were increased by about 50% by infusion of fructose. Thus it is concluded that the stimulation of hepatic ethanol uptake by fructose is dependent on the presence of ADH. Unexpectedly, fructose decreased rates of ethanol metabolism and H2O2 generation by about 60% in perfused livers from ADH-negative deermice, probably by decreasing activation of fatty acids and thus diminishing rates of peroxisomal beta-oxidation.

Alcohol Dehydrogenase↗
PubMed1985

Role of alcohol dehydrogenase in the swift increase in alcohol metabolism (SIAM). Studies with deer mice deficient in alcohol dehydrogenase.

Previous studies have shown that rates of ethanol metabolism increase markedly 2-4 hr after the administration of ethanol in rats and in four inbred strains of mice. This phenomenon, called the swift increase in alcohol metabolism (SIAM), also exists in humans. To determine whether alcohol dehydrogenase (ADH) is necessary for the SIAM response, we compared ethanol metabolism in two strains of the deer mouse, Peromyscus maniculatus. One strain lacks alcohol dehydrogenase (ADH-negative), whereas the other strain has normal ADH levels (ADH-positive). Rates of ethanol elimination were determined after a single intraperitoneal injection of ethanol at different doses (0.5 to 3.0 g/kg) and also after both strains were exposed to various levels of ethanol vapor for 4 hr. The ADH-positive strain exhibited up to a 72% increase in the rate of ethanol elimination after exposure to ethanol vapor compared to the ethanol-injected controls. In contrast, treatment with ethanol vapor did not alter rates of ethanol elimination in the ADH-negative strain. These data demonstrate clearly that ADH is required for SIAM in the deer mouse. In addition, in both the ADH-positive and the ADH-negative strain, rates of ethanol elimination increased in both the ethanol-injected and vapor-treated groups 2- to 3-fold as the dose of ethanol was increased from 100 to 500 mg/100 ml. Thus, it is concluded that this "concentration effect" of ethanol on rates of ethanol metabolism does not involve ADH in the . deer mouse.

Alcohol Dehydrogenase↗