PMID- 18824010
OWN - NLM
STAT- MEDLINE
DCOM- 20081216
LR  - 20191210
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 233
IP  - 2
DP  - 2008 Dec 1
TI  - Cytochrome P450-mediated activation of the fragrance compound geraniol forms 
      potent contact allergens.
PG  - 308-13
LID - 10.1016/j.taap.2008.08.014 [doi]
AB  - Contact sensitization is caused by low molecular weight compounds which penetrate 
      the skin and bind to protein. In many cases, these compounds are activated to 
      reactive species, either by autoxidation on exposure to air or by metabolic 
      activation in the skin. Geraniol, a widely used fragrance chemical, is considered 
      to be a weak allergen, although its chemical structure does not indicate it to be 
      a contact sensitizer. We have shown that geraniol autoxidizes and forms 
      allergenic oxidation products. In the literature, it is suggested but not shown 
      that geraniol could be metabolically activated to geranial. Previously, a 
      skin-like CYP cocktail consisting of cutaneous CYP isoenzymes, was developed as a 
      model system to study cutaneous metabolism. In the present study, we used this 
      system to investigate CYP-mediated activation of geraniol. In incubations with 
      the skin-like CYP cocktail, geranial, neral, 2,3-epoxygeraniol, 6,7-epoxygeraniol 
      and 6,7-epoxygeranial were identified. Geranial was the main metabolite formed 
      followed by 6,7-epoxygeraniol. The allergenic activities of the identified 
      metabolites were determined in the murine local lymph node assay (LLNA). 
      Geranial, neral and 6,7-epoxygeraniol were shown to be moderate sensitizers, and 
      6,7-epoxygeranial a strong sensitizer. Of the isoenzymes studied, CYP2B6, CYP1A1 
      and CYP3A5 showed high activities. It is likely that CYP1A1 and CYP3A5 are mainly 
      responsible for the metabolic activation of geraniol in the skin, as they are 
      expressed constitutively at significantly higher levels than CYP2B6. Thus, 
      geraniol is activated through both autoxidation and metabolism. The allergens 
      geranial and neral are formed via both oxidation mechanisms, thereby playing a 
      large role in the sensitization to geraniol.
FAU - Hagvall, Lina
AU  - Hagvall L
AD  - Department of Chemistry, Dermatochemistry and Skin Allergy, University of 
      Gothenburg, SE-412 96 Gothenburg, Sweden.
FAU - Baron, Jens Malte
AU  - Baron JM
FAU - Borje, Anna
AU  - Borje A
FAU - Weidolf, Lars
AU  - Weidolf L
FAU - Merk, Hans
AU  - Merk H
FAU - Karlberg, Ann-Therese
AU  - Karlberg AT
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080910
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Acyclic Monoterpenes)
RN  - 0 (Allergens)
RN  - 0 (Epoxy Compounds)
RN  - 0 (Monoterpenes)
RN  - 0 (Perfume)
RN  - 0 (Terpenes)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
RN  - EC 1.14.14.1 (CYP2B6 protein, human)
RN  - EC 1.14.14.1 (CYP3A5 protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2B6)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.5.- (Oxidoreductases, N-Demethylating)
RN  - L837108USY (geraniol)
RN  - T7EU0O9VPP (citral)
SB  - IM
MH  - Acyclic Monoterpenes
MH  - Allergens/*chemistry/metabolism
MH  - Animals
MH  - Aryl Hydrocarbon Hydroxylases/metabolism
MH  - Cytochrome P-450 CYP1A1/metabolism
MH  - Cytochrome P-450 CYP2B6
MH  - Cytochrome P-450 CYP3A/metabolism
MH  - Cytochrome P-450 Enzyme System/*metabolism
MH  - Dermatitis, Allergic Contact/*etiology
MH  - Epoxy Compounds/chemistry/metabolism/toxicity
MH  - Humans
MH  - Local Lymph Node Assay
MH  - Mice
MH  - Monoterpenes/metabolism/toxicity
MH  - Oxidation-Reduction
MH  - Oxidoreductases, N-Demethylating/metabolism
MH  - Perfume/chemistry/*toxicity
MH  - Terpenes/metabolism/*toxicity
EDAT- 2008/10/01 09:00
MHDA- 2008/12/17 09:00
CRDT- 2008/10/01 09:00
PHST- 2008/06/27 00:00 [received]
PHST- 2008/08/27 00:00 [revised]
PHST- 2008/08/28 00:00 [accepted]
PHST- 2008/10/01 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/10/01 09:00 [entrez]
AID - S0041-008X(08)00365-7 [pii]
AID - 10.1016/j.taap.2008.08.014 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2008 Dec 1;233(2):308-13. doi: 
      10.1016/j.taap.2008.08.014. Epub 2008 Sep 10.