Skin Sensitization: Reaction Mechanistic Applicability Domains for Computational Structure Activity Relationship
A POJECT REPORT
AS PART OF THE REQUIRMENT OF
THE DEGREE OF MASTER OF SCIENCE
BALDANIYA BHAVESHKUMAR B.
Enrollment no: CUG/2011/0193
SCHOOL OF ChEMICAL SCIENCEs
Central University of Gujarat
GAndhinagar – 382030
Dedicated to my
Parents And Friends
I hereby declare that the work exemplified in this dissertation is the result of investigations carried out by me in the School of Chemical Sciences, Central University of Gujarat, Gandhinagar, under the supervision of Prof. Prakash C. Jha.
Prof. Prakash C. Jha.
Baldaniya Bhaveshkumar B.
Date: May 2013
Introduction of skin sensitization:
Skin sensitization is an important industrial disease. Sensitization of workers and consumers is a major problem for individuals, employers and for marketing certain products. In western world, 15-20% of the populations are allergic to one or more chemicals in their environment.1 Skin sensitization are reactive toxicity end point. Skin sensitization is caused by very wide range of chemicals. Skin sensitization is an immune reaction to small exogenous molecules with the ability to chemically modify skin proteins.2 Skin sensitizers are reacting on the surface of skin proteins of human or animal. The proteins modified with the chemicals are then recognized by the immune system as foreign particle and trigger a specific T-cell mediated immune response leading to the disease status known as contact allergy. A key step in this process is that covalent adduct between skin sensitizers and endogenous protein or peptide in the skin.2 In the immune system of body there is large chain of protein molecules, that protein part is known as epitopes. Epitopes are reacting as receptor in the skin and sensitizers are binding to modify the skin.3 Mainly, skin sensitization process is involving two steps. First is introduction of skin sensitizers to expose skin proteins and second step is sensitizers reaction with immune system.2 The skin sensitizer compound either as such or after metabolic or abiotic (like increasing or decreasing temperature) conversion; binds covalently to skin proteins acting in most cases as an electrophile towards nucleophile groups on the proteins, leading to the formation of antigens which binds with Y-shape proteins known as antibodies.4 There are several recent publications on skin sensitization to aldehyde and ketones, which can sensitize by covalently binding to skin protein via Schiff base formation.4
Mechanism of skin sensitization:
Skin sensitization is happening in two phase which given below: 1. Induction of sensitization phase
2. Elicitation of sensitization phase
This whole process is done in eleven steps. That all steps are given below, some steps coming under induction and some in elicitation.5 1) Induction of sensitization phase
i) Attack of the allergen to the epidermis of the body through the outer layer of skin ii) Binding of chemicals (allergens) to the surface of antigen presenting cells iii) Metabolism to reactive hapten (in the body hapten acting as a carrier of foreign particle) iv) Hapten reacting with the cellular protein to form antigen v) Processing of antigen by the cell including its presentation on the outer surface of the cell in association with genetically determined major histocompatibility complex (MHC) trans cellular glycoproteins vi) Passage of antigen bearing cells to lymph nodes
vii) Allowance of antigen by specific T-cells
viii) Expansion of specific T-cells having allergens and their spreading around the body by the blood system 2) Elicitation of sensitization phase
ix) Repetition of stages I-V
x) Launching of the allergen containing antigen to the enlarge population of specific T-cells in skin xi) Production of...
References: 1) Allergic Contact Dermatitis - Formation, Structural Requirements, and Reactivity of Skin Sensitizers. Chem. Res. Toxicol. 2008, 21, 53-69
2) Chemical Basis for the Extreme Skin sensitization Potency of (E)-4-(Ethoxymethylene)-2-phenyloxazol-5-(4H)-one. Chem. Res. Toxicol. 2010, 23, 1913-1920
3) Chemical Reactivity and Skin Sensitization Potential for Benzaldehydes: Can Schiff Base Formation Explain Everything? Chem. Res. Toxicol. 2012, 25, 2203-2215
4) Mechanistic Applicability Domains for Non-Animal Based Prediction of Toxicological Endpoints. QSAR Analysis of the Schiff Base Applicability Domain for Skin Sensitization. Chem. Res. Toxicol. 2006, 19, 1228-1233
5) Structure Activity Relationship for Skin Sensitization Potential: Development of Structural Alerts for Use in Knowledge-Based Toxicity Prediction Systems. J. Chem. Inf. Comput. Sci. 1994, 34, 154-161
6) An introduction to medicinal chemistry by Graham L. Patrick
7) Statistical concept in QSAR, S. Moro – MACF, 2002
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