PMID- 28121139
OWN - NLM
STAT- MEDLINE
DCOM- 20170717
LR  - 20180814
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 30
IP  - 2
DP  - 2017 Feb 20
TI  - Structure-Potency Relationships for Epoxides in Allergic Contact Dermatitis.
PG  - 524-531
LID - 10.1021/acs.chemrestox.6b00241 [doi]
AB  - Epoxides are known or proposed to be involved in skin sensitization in various 
      ways. Some are encountered directly, and others have been shown to be formed 
      abiotically and metabolically from various unsaturated chemicals. They can react 
      as S(N)2 electrophiles. To date no quantitative mechanistic models (QMMs) are 
      known for skin sensitization potency of this subcategory of S(N)2 electrophiles. 
      Here we have considered the reaction mechanistic chemistry of epoxides and 
      combined published experimental kinetic data (rate constants k for reaction with 
      a cysteine-based peptide) together with calculated hydrophobicity data (logP) to 
      derive a QMM correlating potency in the local lymph node assay (LLNA), expressed 
      as EC3, with a relative alkylation index (RAI, calculated as logk + 0.4 logP). 
      The QMM equation, pEC3 = 2.42(+/-0.26) RAI + 4.04 (+/-0.25), n = 9, R(2) = 0.928, 
      R(2)(adj) = 0.917, F = 90, s = 0.18, fits the data well, with one positive 
      outlier. The outlier can be rationalized by its exhibiting an alert for oxidation 
      of an amine moiety to give, in this case, the highly reactive glycidaldehyde. The 
      epoxide QMM predicts the potency of a nonepoxide S(N)2 electrophile (predicted 
      EC3, 0.48%; observed EC3, 0.5%), which suggests that it could form the basis for 
      a more general H-polar S(N)2 QMM that could be a valuable tool in skin 
      sensitization risk assessment for this quite extensive and structurally diverse 
      reaction mechanistic domain.
FAU - Roberts, David W
AU  - Roberts DW
AD  - School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , 
      Liverpool L3 3AF, United Kingdom.
FAU - Aptula, Aynur
AU  - Aptula A
AD  - Unilever Safety and Environmental Assurance Centre, Colworth Science Park, 
      Sharnbrook, Bedford MK44 1LQ, United Kingdom.
FAU - Api, Anne Marie
AU  - Api AM
AD  - Research Institute for Fragrance Materials, Inc. , 50 Tice Boulevard, Woodcliff 
      Lake, New Jersey 07677, United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170125
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Epoxy Compounds)
SB  - IM
MH  - Animals
MH  - Dermatitis, Allergic Contact/*etiology
MH  - Epoxy Compounds/*chemistry/*toxicity
MH  - Humans
MH  - Models, Theoretical
MH  - Structure-Activity Relationship
EDAT- 2017/01/26 06:00
MHDA- 2017/07/18 06:00
CRDT- 2017/01/26 06:00
PHST- 2017/01/26 06:00 [pubmed]
PHST- 2017/07/18 06:00 [medline]
PHST- 2017/01/26 06:00 [entrez]
AID - 10.1021/acs.chemrestox.6b00241 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2017 Feb 20;30(2):524-531. doi: 10.1021/acs.chemrestox.6b00241. 
      Epub 2017 Jan 25.