title: Cinnamic compound metabolism in human skin and the role metabolism may play in determining relative sensitisation potency.
abstract: BACKGROUND
  trans-Cinnamaldehyde and trans-cinnamic alcohol cause allergic contact dermatitis (ACD) in humans; cinnamaldehyde is a more potent sensitiser than cinnamic alcohol. These two chemicals are principal constituents of the European Standard 'Fragrance Mix', as used in patch testing diagnostics of sensitisation to fragrances by clinical dermatologists. As contact sensitisers are usually protein reactive compounds, it is hypothesised that cinnamic alcohol (not protein-reactive) is a 'prohapten' that requires metabolic activation, presumably by cutaneous oxidoreductases, to the protein-reactive cinnamaldehyde (a 'hapten'). It is postulated that cinnamaldehyde can be detoxified by aldehyde dehydrogenase (ALDH) to cinnamic acid and/or by alcohol dehydrogenase (ADH) to cinnamic alcohol. Hence, a variety of metabolic pathways may contribute to the relative exposures and hence sensitising potencies of cinnamic alcohol and cinnamaldehyde.
  
  
  OBJECTIVE
  To evaluate the extent of cinnamaldehyde and cinnamic alcohol metabolism in human skin and provide evidence for the role of cutaneous ADH and ALDH in such metabolism.
  
  
  METHODS
  The extent of cinnamic alcohol and aldehyde metabolism was investigated in human skin homogenates and sub-cellular fractions. A high performance liquid chromatography method was used for analysis of skin sample extracts. Studies were conducted in the presence and absence of the ADH/cytochrome P450 inhibitor 4-methylpyrazole and the cytosolic ALDH inhibitor, disulfiram.
  
  
  RESULTS
  Differential metabolism of cinnamic alcohol and cinnamaldehyde was observed in various subcellular fractions: skin cytosol was seen to be the major site of cinnamic compound metabolism. Significant metabolic inhibition was observed using 4-methylpyrazole and disulfiram in whole skin homogenates and cytosolic fractions only.
  
  
  CONCLUSIONS
  This study has demonstrated that cutaneous ADH and ALDH activities, located within defined subcellular compartments, play important roles in the activation and detoxification of CAlc and CAld in skin. Such findings are important to the development of computational hazard prediction tools for sensitisation (e.g. the DEREK program) and also to dermatologists in understanding observed interindividual differences, cross-reactivities or co-sensitisation to different cinnamic compounds in the clinic.
authors.affiliation: Molecular Toxicology, Section of Biological Chemistry, Division of Biomedical Sciences, Sir Alexander Fleming Building, Imperial College School of Medicine, South Kensington, London SW7 2AZ, UK.
authors.forename: Connie
authors.initials: C
authors.lastname: Cheung
authors.forename: Sharon A M
authors.initials: SA
authors.lastname: Hotchkiss
authors.forename: Camilla K Smith
authors.initials: CK
authors.lastname: Pease
mesh_terms: D000171:Acrolein / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics; D000328:Adult; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D003877:Dermatitis, Contact / Q000209:etiology*; D004221:Disulfiram / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D000077604:Fomepizole; D006358:Hot Temperature; D006801:Humans; D008658:Inactivation, Metabolic; D020005:Propanols / Q000009:adverse effects* / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000494:pharmacology; D012867:Skin / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D020005:Propanols; D011720:Pyrazoles; D000171:Acrolein; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase; D000446:Aldehyde-Lyases; C043439:aldehyde decarbonylase; C012843:cinnamaldehyde; C020722:cinnamyl alcohol; D004221:Disulfiram