Stereospecificity of the sensory irritation receptor for nonreactive chemicals illustrated by pinene enantiomers

Abstract

To clarify the existence of a receptor protein for sensory irritants in trigeminal nerve endings, D- [i.e. (+)] and L- [i.e. (-)] enantiomers of alpha- and beta-pinene as models of nonreactive chemicals were evaluated for their potency in outbred OF1 and NIH/S mice using ASTM E981-84 bioassay. All pinenes possess sensory irritation properties and also induced sedation and signs of anaesthesia but had no pulmonary irritation effects. According to the ratio of RD50 (i.e. concentration which causes a 50% decrease in respiratory rate,f) and vapour pressure (Po), all pinenes are nonreactive chemicals. For nonreactive chemicals, Po and olive oil-gas partition (Loil) can be used to estimate their potency as sensory irritant. Thus, for enantiomers with identical physicochemical properties, the estimated RD50 values are the same. In addition, although alpha- and beta-pinene do not have identical Po and Loil values, their estimated potencies are quite close. However, the experimental results showed that D-enantiomers of pinenes were the most potent as sensory irritants and a difference in potency also exists between alpha- and beta-pinene. RD50 for D-enantiomers of alpha- and beta-pinene were almost equal, 1053 ppm and 1279 ppm in OF1 strain and 1107 ppm and 1419 ppm in NIH/S strain, respectively. Values differed by a factor of approximately 4 to 5 from L-beta-pinene for which the RD50 was 4663 ppm in OF1 and 5811 ppm in NIH/S mice. RD50 could not be determined for L-alpha-pinene; this pinene was almost inactive. D-alpha-pinene seems to best fit the receptor because its experimental RD50 was one-half of the estimated value while for D-beta-pinene those values were equal. On the contrary, L-beta-pinene was about 3 to 4 times less potent than estimated. L-alpha-pinene was only slightly active although it was estimated to be as potent as D-alpha-pinene. The remarkable difference in potency between L-enantiometers is most likely due to a structural difference between alpha- and beta-pinene: the more flexible beta-pinene can bend to fit into the receptor better than the rigid alpha-pinene. The results showed that the commonly used physicochemical descriptors cannot fully explain the potency of these chemicals; their three-dimensional structure should also be considered. Because of the stereospecificity of pinenes, a target site for nonreactive sensory irritants is most likely a receptor protein containing a chiral lipophilic pocket.

Anesthesia and transport of fat snook Centropomus parallelus with the essential oil of Nectandra megapotamica(Spreng.) Mez

“…Both α-and β-pinene have been reported as sedatives (Mercier et al, 2009) and analgesics (Erazo et al, 2006). Kasanen et al (1998) also reported that all pinenes induced sedation followed by signs of anesthesia in mice. Moreover, α-pinene is reported as positive modulator of GABA A receptors (Aoshima & Hamamoto, 1999).…”

The essential oil of turpentine and its major volatile fraction (α- and β-pinenes): a review

“…First of all, a significant quantity is needed for the product to produce adverse health effects: as reported by Menezes et al [89], the toxic effect for the mice starts at 5 g/kg. Kasanen et al [90] postulated that it is highly unlikely that monoterpenes alone can cause irritation under normal conditions ("all pinenes possess sensory irritation properties and also induced sedation and sign of anaesthesia but had no pulmonary irritation effects"). Fransman et al [91] observed that the respiratory problems referring to laminated wood workers were associated with the presence of formaldehyde among all the agents that these people inhaled at work (dust, bacterial endotoxins, abietic acid, formaldehyde and terpenes).…”

Source apportionment of exposure to toxic volatile organic compounds using positive matrix factorization

“…Mass fractions of each factor were scaled by unitless irritancy factors ( IFs ) to determine contributions of each source to total irritancy for a given participant. IFs are calculated using RD 50 values (Ten Brinke, 1995;Kasanen et al, 1998 ), or the concentration of airborne irritant causing a 50% decrease in the respiratory rate of an animal. The RD 50 for toluene is divided by the RD 50 for the compound of interest (Ten Brinke, 1995 ).…”

“…The RD 50 for toluene is divided by the RD 50 for the compound of interest (Ten Brinke, 1995 ). Compounds for which IFs were available (Ten Brinke, 1995;Kasanen et al, 1998 ) and that were included in this calculation are indicated in Table 1. Using these IFs, the greatest irritancy -weighted contribution to exposure in NJ is from Factor 5p (p -DCB ) , which contributes an average of 48% of irritancy.…”