Cutaneous metabolism of glycol ethers.
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.
Lockley
David J
DJ
Skin Toxicology Group, Department of Environmental and Occupational Medicine, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, NE2 4HH, UK. David.Lockley@Unilever.com
Howes
Douglas
D
Williams
Faith M
FM
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000427:Alcohol Deterrents / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D005026:Ethylene Glycols / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000201:enzymology / Q000378:metabolism*; D012869:Skin Absorption; D012997:Solvents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics
D000427:Alcohol Deterrents; D004791:Enzyme Inhibitors; D005026:Ethylene Glycols; D011720:Pyrazoles; D012997:Solvents; D009243:NAD; D000431:Ethanol; C031280:pyrazole; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram