X-Message-Number: 30191
Date: Fri, 21 Dec 2007 10:37:40 -0800 (PST)
From: 
Subject: effect of disulfiram on metabolism of glycol ether

[Snip: "Disulfiram completely inhibited alcohol and glycol ether
metabolism in the liver and skin cytosolic fractions."]

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.
  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

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