Oxidative Tryptophan Modification by Terpene- and Squalene-Hydroperoxides and a Possible Link to Cross-Reactions in Diagnostic Tests

Abstract

Hydroperoxides can act as specific haptens and oxidatively modify proteins. Terpene hydroperoxides trigger unusually high frequencies of positive skin reactions in human patients if tested at high concentrations. It is unknown whether this is due to specific hapten formation. Here, we show that both terpene hydroperoxides and the endogenous hydroperoxide formed from squalene can oxidatively modify tryptophan. Oxidative modifications of Trp were recently postulated to explain cross-sensitization between unrelated photosensitizers. Current observations may extend this hypothesis: Oxidative events triggered by endogenous hydroperoxides and hydroperoxides/oxidants derived from xenobiotics might lead to a sensitized state detected by patch tests with high concentrations of hydroperoxides.

Can contact allergy to p‐phenylenediamine explain the high rates of terpene hydroperoxide allergy? – An epidemiological study based on consecutive patch test results

“…As summarized in Fig. , it has previously been shown that NFK [1] can be formed from Trp [2] when it is exposed to Lin‐OOHs [3] and Lim‐OOHs [4] , p ‐benzoquinone diimines [5] and ketoprofen under ultraviolet (UV) irradiation [6] . It is of note that the activation mechanism through UV irradiation is specific for photosensitizers such as ketoprofen, which absorbs UV light, leading to the formation of singlet oxygen that can react with amino acids such as Trp.…”

“…The authors hypothesized that the formation of a possible immunogenic molecule, enhanced by the presence of ketoprofen but not containing any ketoprofen derivatives, could provide a possible explanation for the clinically observed cross‐reactivity between ketoprofen and structurally unrelated molecules. These results have yet to be confirmed, and the application of the above hypothesis, as performed by Natsch et al , to the case of frequent patch test reactivity to Lin‐OOHs and Lim‐OOHs has been criticized for several reasons . Previously, both mechanistic studies and animal studies have provided evidence against general cross‐reactivity between terpene hydroperoxides .…”

“…It has recently been hypothesized by fragrance industry that positive patch test reactions to these terpene hydroperoxides may not always represent a hapten‐specific sensitization state, but could also be associated with a state of reactivity to multiple degradation products formed under oxidative conditions. Thus, Natsch et al proposed that oxidative modifications of tryptophan (Trp) residues on skin proteins, namely N ‐formyl kynurenine (NFK), caused by various sources, could lead to a sensitized state detected by patch testing with the terpene hydroperoxides .…”

One hundred years of allergic contact dermatitis due to oxidized terpenes: What we can learn from old research on turpentine allergy

“…The contribution of air‐oxidized terpenes to allergic contact dermatitis (ACD) has generated a lot of interest over the past two decades (over 300 entries in Contact Dermatitis based on the keywords terpene and oxidation) mainly in connection with fragrance allergies. Although numerous articles have clearly demonstrated that terpenes can react with air to form oxidation products, 1,2 that these oxidation products (mainly hydroperoxides) are very potent skin allergens, 3 that these oxidized chemicals can elicit positive skin reactions in patients by either patch testing 4‐8 or repeated open application test (ROAT), 9,10 the contribution/relevance of these terpene oxidation products to fragrance skin allergy remains a matter of debate 11 . As very often, the critical point and/or the missing link is the exposure assessment!…”

“…Although numerous articles have clearly demonstrated that terpenes can react with air to form oxidation products, 1,2 that these oxidation products (mainly hydroperoxides) are very potent skin allergens, 3 that these oxidized chemicals can elicit positive skin reactions in patients by either patch testing [4][5][6][7][8] or repeated open application test (ROAT), 9,10 the contribution/relevance of these terpene oxidation products to fragrance skin allergy remains a matter of debate. 11 As very often, the critical point and/or the missing link is the exposure assessment! Difficulties in tracing exposure, based on analysis of fragrance products, are often used to challenge the contribution of these oxidation products to the induction of skin allergies.…”