In vivo contribution of Class III alcohol dehydrogenase (ADH3) to alcohol metabolism through activation by cytoplasmic solution hydrophobicity

Haseba, Takeshi; Duester, Gregg; Shimizu, Akio; Yamamoto, Isao; Kameyama, Koji; Ohno, Youkichi

doi:10.1016/j.bbadis.2005.11.008

Cited by 34 publications

(45 citation statements)

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“…Increased expression of pgls could contribute to decreased lifetime of 6-phosphogluconolactone, its highly reactive and potentially toxic substrate. Alcohol dehydrogenase class-3 ( adh3 ) , also induced, constitutes the primary defence mechanism against formaldehyde damage and may also indirectly mediate protection of proteins against oxidation [71]. Gene encoding heme oxygenase 1 ( ho-1 ) that has important antioxidant and cytoprotective activities was the most highly induced gene by dietary GLs in muscle (Table 7).…”

Section: Resultsmentioning

confidence: 99%

Nutrigenomic effects of glucosinolates on liver, muscle and distal kidney in parasite-free and salmon louse infected Atlantic salmon

Skugor¹,

Holm

Bjelland³

et al. 2016

Parasites Vectors

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BackgroundReduction of Lepeophtheirus salmonis infection in Atlantic salmon achieved by glucosinolates (GLs) from Brassica plants was recently reported. However, wider application of functional feeds based on GLs requires better knowledge of their positive and adverse effects.MethodsLiver, distal kidney and muscle transcriptomes of salmon exposed to the extreme dose of GLs were profiled by microarray, while qPCR analysis followed up selected hepatic and renal responses under the extreme and moderate GLs dose during the L. salmonis challenge. Transcriptional analysis were complemented with measurements of organ indices, liver steatosis and plasma profiling, including indicators of cytolysis and bilirubin. Finally, the third trial was performed to quantify the effect of lower GLs doses on growth.ResultsThe extreme GLs dose caused a decrease in hepatic fat deposition and growth, in line with microarray findings, which suggested tissue remodeling and reduction of cellular proliferation in the skeletal muscle and liver. Lower GLs inclusion levels in a follow-up trial did not show negative effects on growth. Microarray analysis of the distal kidney pointed to activation of anti-fibrotic responses under the overexposure. However, analyses of ALT, CK and AST enzymes in plasma provided no evidence of increased cytolysis and organ damage. Prevalent activation of phase-2 detoxification genes that occurred in all three tissues could be considered part of beneficial effects caused by the extreme dose of GLs. In addition, transcriptomic evidence suggested GLs-mediated iron and heme withdrawal response, including increased heme degradation in muscle (upregulation of heme oxygenase-1), decrease of its synthesis in liver (downregulation of porphobilinogen deaminase) and increased iron sequestration from blood (hepatic induction of hepcidin-1 and renal induction of intracellular storage protein ferritin). This response could be advantageous for salmon upon encountering lice, which depend on the host for the provision of iron carrying heme. Most of the hepatic genes studied by qPCR showed similar expression levels in fish exposed to GLs, lice and their combination, while renal induction of leptin suggested heightened stress by the combination of extreme dose of GLs and lice. High expression of interferon γ (cytokine considered organ-protective in mammalian kidney) was detected at the moderate GLs level. This fish also showed highest plasma bilirubin levels (degradation product of heme), and had lowest number of attached lice, further supporting hypothesis that making heme unavailable to lice could be part of an effective anti-parasitic strategy.ConclusionsModulation of detoxification and iron metabolism in Atlantic salmon tissues could be beneficial prior and during lice infestations. Investigation of anti-lice functional feeds based on low and moderate GLs inclusion levels thus deserves further attention.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1921-7) contains supplementary mater...

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Section: Resultsmentioning

confidence: 99%

Nutrigenomic effects of glucosinolates on liver, muscle and distal kidney in parasite-free and salmon louse infected Atlantic salmon

Skugor¹,

Holm

Bjelland³

et al. 2016

Parasites Vectors

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“…This pyrazole-insensitive pathway has a greater metabolic role when the level of blood alcohol is high or when the intake of alcohol is chronic [2–7]. Recently, we used ADH1-null mice to show that ADH1 accounts for about 70% of systemic alcohol metabolism [25,26], which means that the non-ADH1 pathway accounts for the remaining 30%. Regarding the identity of the main enzyme responsible for this pathway, a heated scientific debate has continued for three decades over whether it is catalase [10–12] or MEOS, which is mainly composed of CYP2E1 [2–9].…”

Section: Historical Debate On the Identification Of Enzyme(s) In The mentioning

confidence: 99%

“…Recently, we used ADH3-null mutant mice to demonstrate that the contribution of ADH3 to alcohol metabolism in vivo increases dose-dependently [25]. …”

Section: Introductionmentioning

confidence: 99%

A New View of Alcohol Metabolism and Alcoholism—Role of the High-Km Class Ⅲ Alcohol Dehydrogenase (ADH3)

Haseba

Ohno

2010

IJERPH

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The conventional view is that alcohol metabolism is carried out by ADH1 (Class I) in the liver. However, it has been suggested that another pathway plays an important role in alcohol metabolism, especially when the level of blood ethanol is high or when drinking is chronic. Over the past three decades, vigorous attempts to identify the enzyme responsible for the non-ADH1 pathway have focused on the microsomal ethanol oxidizing system (MEOS) and catalase, but have failed to clarify their roles in systemic alcohol metabolism. Recently, using ADH3-null mutant mice, we demonstrated that ADH3 (Class III), which has a high Km and is a ubiquitous enzyme of ancient origin, contributes to systemic alcohol metabolism in a dose-dependent manner, thereby diminishing acute alcohol intoxication. Although the activity of ADH3 toward ethanol is usually low in vitro due to its very high Km, the catalytic efficiency (kcat/Km) is markedly enhanced when the solution hydrophobicity of the reaction medium increases. Activation of ADH3 by increasing hydrophobicity should also occur in liver cells; a cytoplasmic solution of mouse liver cells was shown to be much more hydrophobic than a buffer solution when using Nile red as a hydrophobicity probe. When various doses of ethanol are administered to mice, liver ADH3 activity is dynamically regulated through induction or kinetic activation, while ADH1 activity is markedly lower at high doses (3–5 g/kg). These data suggest that ADH3 plays a dynamic role in alcohol metabolism, either collaborating with ADH1 or compensating for the reduced role of ADH1. A complex two-ADH model that ascribes total liver ADH activity to both ADH1 and ADH3 explains the dose-dependent changes in the pharmacokinetic parameters (β, CLT, AUC) of blood ethanol very well, suggesting that alcohol metabolism in mice is primarily governed by these two ADHs. In patients with alcoholic liver disease, liver ADH3 activity increases, while ADH1 activity decreases, as alcohol intake increases. Furthermore, ADH3 is induced in damaged cells that have greater hydrophobicity, whereas ADH1 activity is lower when there is severe liver disease. These data suggest that chronic binge drinking and the resulting liver disease shifts the key enzyme in alcohol metabolism from low-Km ADH1 to high-Km ADH3, thereby reducing the rate of alcohol metabolism. The interdependent increase in the ADH3/ADH1 activity ratio and AUC may be a factor in the development of alcoholic liver disease. However, the adaptive increase in ADH3 sustains alcohol metabolism, even in patients with alcoholic liver cirrhosis, which makes it possible for them to drink themselves to death. Thus, the regulation of ADH3 activity may be important in preventing alcoholism development.

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“…We have previously shown that ethanol-mediated expression of RANTES (regulated upon activation normal T cell expressed and secreted) and endothelin-1 was dose-dependent (25-100 mM) with optimal expression at 100 mM ethanol (38,39); thus, we utilized this dose of ethanol for studies described herein. Although this concentration of alcohol (0.46%) may seem physiologically high, studies (40) show that the metabolism of ethanol increases to accommodate increased alcohol intake in chronic alcoholics. Treatment of C-rKCs with ethanol (100 mM) showed 3-and 7-fold increase in HO-1 mRNA expression at 12 and 24 h, respectively.…”

Section: Ethanol Augments Ho-1 and Hif-1␣ Mrna Expression Inmentioning

confidence: 99%

Ethanol-induced HO-1 and NQO1 Are Differentially Regulated by HIF-1α and Nrf2 to Attenuate Inflammatory Cytokine Expression

Yeligar

Machida

Kalra

2010

Journal of Biological Chemistry

127

167

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In vivo contribution of Class III alcohol dehydrogenase (ADH3) to alcohol metabolism through activation by cytoplasmic solution hydrophobicity

Cited by 34 publications

References 38 publications

Nutrigenomic effects of glucosinolates on liver, muscle and distal kidney in parasite-free and salmon louse infected Atlantic salmon

Nutrigenomic effects of glucosinolates on liver, muscle and distal kidney in parasite-free and salmon louse infected Atlantic salmon

A New View of Alcohol Metabolism and Alcoholism—Role of the High-Km Class Ⅲ Alcohol Dehydrogenase (ADH3)

Ethanol-induced HO-1 and NQO1 Are Differentially Regulated by HIF-1α and Nrf2 to Attenuate Inflammatory Cytokine Expression

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