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
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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
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