Activation of the endoperoxide ascaridole modulates its sensitizing capacity

Abstract

The monoterpene ascaridole, a fairly stable endoperoxide found in essential oils such as tea tree oil can provoke allergic contact dermatitis which has been evidenced under patch test conditions. However, concomitantly we observed irritative skin reactions that demand further data underlining the sensitization potential of ascaridole. Here, we studied the effects of ascaridole on dendritic cell (DC) activation and protein reactivity, 2 key steps of chemical-induced skin sensitization. Treatment of human monocyte-derived DC with ascaridole found support for full DC maturation, a capability of sensitizers but not irritants. It induced significant upregulation of the expression of the costimulatory molecules CD86, CD80, CD40, and the adhesion molecule CD54 in a time-dependent manner. Maturation was accompanied by release of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor-a, IL-6, and IL-8. Similar to other chemical skin sensitizers including hydroperoxides, we observed a certain reactivity of ascaridole toward cysteine-but not lysinecontaining peptides. During recent years, evidence accumulated for a radical mechanism as trigger for protein reactivity of peroxides. Treatment of the fairly stable endoperoxide ascaridole with iron as radical inducer ("activated ascaridole") resulted in cysteine peptide reactivity exceeding by far that of ascaridole itself. Furthermore, activated ascaridole showed increased potential for induction of the Nrf2 target gene heme oxygenase 1 and upregulation of CD86 and CD54 on THP-1 cells, an established DC surrogate. These results indicate that radical formation could be involved in the steps leading to skin sensitization induced by the endoperoxide ascaridole.

Interaction of ascaridole, carvacrol, and caryophyllene oxide from essential oil of Chenopodium ambrosioides L. with mitochondria in Leishmania and other eukaryotes

“…Car, Caryo, and Asc showed antileishmanial activity, although they were less selective for Leishmania in comparison with mammalian host cells than EO for Leishmania compared with effects on mammalian host cells (Monzote et al, ; Monzote, Garcia, et al, ). Asc, which is also present in tea tree oil, demonstrated a skin‐sensitizing effect in mammals (Chittiboyina, Avonto, & Khan, ; Krutz et al, ). By the use of iron chelators, it was shown that activation of the endoperoxide Asc in EO by iron is essential for its antiparasitic actions.…”