Chemical reaction: Cross-reactivity is patient-specific due to skin metabolism

April 30, 2009

Chemicals can cause skin sensitization or undergo a process where they transform into skin sensitizers. Some patients are more susceptible to sensitization than others. Cross-reactivity is a reaction that is individualized, and cross-reactivity can occur with one patient and not with another.

Strasbourg, France ’ Chemicals can be skin sensitizers in and of themselves, or they can undergo a transformation process and become reactive and transform into skin sensitizers, according to a leading researcher in contact dermatitis.

Jean-Pierre Lepoittevin, Ph.D., professor in the department of chemistry, Université Louis Pasteur in Strasbourg, France, describes the role of haptens in allergic contact dermatitis in a keynote address here to dermatologists.

He says that two-thirds of all chemicals are real haptens, or low molecular weight molecules that are sufficiently lipophilic to penetrate the epidermis through the stratum corneum. In order to cause sensitization, a compound has to penetrate the skin, where it may be metabolized and react with epidermal proteins to form new chemical structures that are recognized as antigenic.

There is a differentiation between real haptens that can react on their own and modify proteins and those that are not reactive and need to be activated through various means.

Dr. Lepoittevin says that haptens have a strong chemical reactivity that allows the formation of a covalent link with nucleophilic residues on protein amino acid chains.


Sensitizing potential

It had been previously thought that overall chemical reactivity of a molecule was suggestive of its sensitizing potential, but it is now hypothesized that the sensitizing potential of a molecule is linked to its chemical reactivity towards a few specific amino acids that are key to the sensitization process, Dr. Lepoittevin tells Dermatology Times.


Delayed hypersensitivity

Dr. Lepoittevin described phenomena around delayed hypersensitivity in patients. Delayed hypersensitivity is the result of chemical reactions and/or interactions during the crossing of the cutaneous barrier, during the formation of the hapten-protein complex, or during the phenomenon of recognition between the antigen and the T-cell receptors.

Some patients can detoxify very efficiently, and some cannot, making those who cannot more susceptible to sensitization, Dr. Lepoittevin says.

"What is important at the clinical level is that all the molecules need to be reactive," he says.


Cross-reactivity

Cross-reactivity is an individualized reaction, and cross-reactivity can occur with one patient and not with another, Dr. Lepoittevin says.

"When you consider cross-reactivity, it’s never absolute," he says. "When skin metabolism is involved, you may have a different situation from one patient to another. The enzymes may be different from one patient to another. You can observe a cross-reaction in one patient and not in another, just because the molecules are not activated in the same way."

Dr. Lepoittevin cites the example of cinnamic alcohol and cinnamic adlehyde, the latter ingredient being found in cosmetic products like deodorants.

"About half of the patients sensitive to cinnamic alcohol will react to cinnamic aldehyde, but half will not," he says. "Some are making another metabolite which is not cross-reacting with cinnamic aldehyde."


Cosmetic industry

Increasingly, the cosmetic industry is introducing new molecules and attempting to be innovative in the contents of new cosmetic products, according to Dr. Lepoittevin.

"They are trying to use new active ingredients for which we don-t know the exact sensitizing potential," Dr. Lepoittevin says. "That is why it is important to understand how all these molecules can react with proteins to predict if they will be skin sensitizers."

Disclosure of ingredients of any new cosmetic products is necessary for researchers to be aware of the molecules contained in new products and to determine safe levels of content for the consumers to avoid possible contact allergy, Dr. Lepoittevin says.In the interest of reducing testing on animals, researchers have been investigating possible

in vitro

alternative tests for skin sensitization, he says.

Some research has highlighted that peptide reactivity can act as a method to classify allergens, with minimal or low peptide reactivity being suggestive of non-allergens or weak allergens, and moderate to high peptide reactivity suggestive of moderate to extremely potent allergens.


Altered state

Dr. Lepoittevin says that haptens could alter proteins for the development of predictive alternative tests aimed at the identification of hazard and potency. Those tests include Structure Activity Relationships and Quantitative Structure Activity Relationships.

The tests have been key in the design of peptide reactivity tests directed at “in chemico” identification of sensitizers. DT