X-Message-Number: 33322
Date: Thu, 10 Feb 2011 18:18:13 -0800 (PST)
From: 
Subject: alcohol dehydrogenase ADH1 ativity in the brain


Alcohol dehydrogenase type 1 in the brain and other tissues can generate toxic 
metabolites from some cryoprotectants. As a consequence, ADH1 inhibitors such as
pyrazole should reduce cryoprotectant toxicity. The question I have is how much
would cryoprotectant toxicity be reduced? As far as I am aware, no published 
cryobiology experiments have examined this aspect of cryoprotectant toxicity.

Eur J Biochem. 2001 Oct;268(19):5045-56.

Distribution of alcohol dehydrogenase mRNA in the rat central nervous system. 
Consequences for brain ethanol and retinoid metabolism.

Martinez SE, Vaglenova J, Sabria J, Martinez MC, Farres J, Pares X. Department 
of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, 
E-08193 Bellaterra (Barcelona), Spain.
Abstract

    The localization of alcohol dehydrogenase (ADH) in brain regions would 
    demonstrate active ethanol metabolism in brain during alcohol consumption, 
    which would be a new basis to explain the effects of ethanol in the central 
    nervous system. Tissue sections from several regions of adult rat brain were
    examined by in situ hybridization to detect the expression of genes 
    encoding ADH1 and ADH4, enzymes highly active with ethanol and retinol. ADH1
    mRNA was found in the granular and Purkinje cell layers of cerebellum, in 
    the pyramidal and granule cells of the hippocampal formation and in some 
    cell types of cerebral cortex. ADH4 expression was detected in the Purkinje 
    cells, in the pyramidal and granule cells of the hippocampal formation and 
    in the pyramidal cells of cerebral cortex. High levels of ADH1 and ADH4 
    mRNAs were detected in the CNS epithelial and vascular tissues: 
    leptomeninges, choroid plexus, ependymocytes of ventricle walls, and 
    endothelium of brain vessels. Histochemical methods detected ADH activity in
    rodent cerebellar slices, while Western-blot analysis showed ADH4 protein 
    in homogenates from several brain regions. In consequence, small but 
    significant levels of ethanol metabolism can take place in distinct areas of
    the CNS following alcohol consumption, which could be related to brain 
    damage caused by a local accumulation of acetaldehyde. Moreover, the 
    involvement of ADH in the synthesis of retinoic acid suggests a role for the
    enzyme in the regulation of adult brain functions. The impairment of 
    retinol oxidation by competitive inhibition of ADH in the presence of 
    ethanol may be an additional origin of CNS abnormalities caused by ethanol.
PMID: 11589695
Free text>
http://www3.interscience.wiley.com/cgi-bin/fulltext/118990598/PDFSTART

Arch Toxicol. 2005 Mar;79(3):160-8. Epub 2004 Nov 17.
Cutaneous metabolism of glycol ethers.

Lockley DJ, Howes D, Williams FM. Skin Toxicology Group, Department of 
Environmental and Occupational Medicine, University of Newcastle-upon-Tyne, 
Newcastle-upon-Tyne, NE2 4HH, UK.
Abstract

  The toxicity of glycol ethers is associated with their oxidation to the 
  corresponding aldehyde and alkoxyacetic acid by cytosolic alcohol 
  dehydrogenase (ADH; EC 1.1.1.1.) and aldehyde dehydrogenase (ALDH; 1.2.1.3). 
  Dermal exposure to these compounds can result in localised or systemic 
  toxicity including skin sensitisation and irritancy, reproductive, 
  developmental and haemotological effects. It has previously been shown that 
  skin has the capacity for local metabolism of applied chemicals. Therefore, 
  there is a requirement to consider metabolism during dermal absorption of 
  these compounds in risk assessment for humans. Cytosolic fractions were 
  prepared from rat liver, and whole and dermatomed skin by differential 
  centrifugation. Rat skin cytosolic fractions were also prepared following 
  multiple dermal exposure to dexamethasone, ethanol or 2-butoxyethanol (2-BE). 
  The rate of ethanol, 2-ethoxyethanol (2-EE), ethylene glycol, 2-phenoxyethanol
  (2-PE) and 2-BE conversion to alkoxyacetic acid by ADH/ALDH in these 
  fractions was continuously monitored by UV spectrophotometry via the 
  conversion of NAD+ to NADH at 340 nm. Rates of ADH oxidation by rat liver 
  cytosol were greatest for ethanol followed by 2-EE >ethylene glycol >2-PE 
  >2-BE. However, the order of metabolism changed to 2-BE >2-PE >ethylene glycol
  >2-EE >ethanol using whole and dermatomed rat skin cytosolic fractions, with 
  approximately twice the specific activity in dermatomed skin cytosol relative 
  to whole rat skin. This suggests that ADH and ALDH are localised in the 
  epidermis that constitutes more of the protein in dermatomed skin than whole 
  skin cytosol. Inhibition of ADH oxidation in rat liver cytosol by pyrazole was
  greatest for ethanol followed by 2-EE >ethylene glycol >2-PE >2-BE, but it 
  only inhibited ethanol metabolism by 40% in skin cytosol. Disulfiram 
  completely inhibited alcohol and glycol ether metabolism in the liver and skin
  cytosolic fractions. Although ADH1, ADH2 and ADH3 are expressed at the 
  protein level in rat liver, only ADH1 and ADH2 are selectively inhibited by 
  pyrazole and they constitute the predominant isoforms that metabolise 
  short-chain alcohols in preference to intermediate chain-length alcohols. 
  However, ADH1, ADH3 and ADH4 predominate in rat skin, demonstrate different 
  sensitivities to pyrazole, and are responsible for metabolising glycol ethers.
  ALDH1 is the predominant isoform in rat liver and skin cytosolic fractions 
  that is selectively inhibited by disulfiram and responds to the amount of 
  aldehyde formed by the ADH isoforms expressed in these tissues. Thus, the 
  different affinity of ADH and ALDH for alcohols and glycol ethers of different
  carbon-chain length may reflect the relative isoform expression in rat liver 
  and skin. Following multiple topical exposure, ethanol metabolism increased 
  the most following ethanol treatment, and 2-BE metabolism increased the most 
  following 2-BE treatment. Ethanol and 2-BE may induce specific ADH and ALDH 
  isoforms that preferentially metabolise short-chain alcohols (i.e. ADH1, 
  ALDH1) and longer chain alcohols (i.e. ADH3, ADH4, ALDH1), respectively. 
  Treatment with a general inducing agent such as dexamethasone enhanced ethanol
  and 2-BE metabolism suggesting induction of multiple ADH isoforms.
PMID: 15551062

Could OTC ranitidine substitute for prescription pyrazole?

Hum Exp Toxicol. 2010 Feb;29(2):93-101. Epub 2009 Dec 21.

Ranitidine as an alcohol dehydrogenase inhibitor in acute methanol toxicity in 
rats.

El-Bakary AA, El-Dakrory SA, Attalla SM, Hasanein NA, Malek HA. Department of 
Forensic Medicine, Histology and Cytology, Faculty of Medicine, Mansoura 
University, Egypt.
Abstract

  Methanol poisoning is a hazardous intoxication characterized by visual 
  impairment and formic acidemia. The therapy for methanol poisoning is alcohol 
  dehydrogenase (ADH) inhibitors to prevent formate accumulation. Ranitidine has
  been considered to be an inhibitor of both gastric alcohol and hepatic 
  aldehyde dehydrogenase enzymes. This study aimed at testing ranitidine as an 
  antidote for methanol acute toxicity and comparing it with ethanol and 
  4-methyl pyrazole (4-MP). This study was conducted on 48 Sprague-Dawley rats, 
  divided into 6 groups, with 8 rats in each group (one negative control group 
  [C1], two positive control groups [C2, C3] and three test groups [1, 2 and 
  3]). C2, C3 and all test groups were exposed to nitrous oxide by inhalation, 
  then, C3 group was given methanol (3 g/kg orally). The three test groups 1, 2 
  and 3 were given ethanol (0.5 g/kg orally), 4-MP (15 mg/kg intraperitoneally) 
  and ranitidine (30 mg/kg intraperitoneally), respectively, 4 hours after 
  giving methanol. Rats were sacrificed and heparinized, cardiac blood samples 
  were collected for blood pH and bicarbonate. Non-heparinized blood samples 
  were collected for formate levels by high performance liquid chromatography. 
  Eye balls were enucleated for histological examination of the retina. 
  Ranitidine corrected metabolic acidosis (p = .025), decreased formate levels 
  (p = .014) and improved the histological findings in the retina induced by 
  acute methanol toxicity.
PMID: 20026516

Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=33322