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

被引:38
作者
Kasanen, JP
Pasanen, AL
Pasanen, P
Liesivuori, J
Kosma, VM
Alarie, Y
机构
[1] Univ Kuopio, Dept Environm Sci, FIN-70211 Kuopio, Finland
[2] Kuopio Reg Inst Occupat Hlth, FIN-70701 Kuopio, Finland
[3] Univ Kuopio, Dept Pathol & Forens Med, FIN-70211 Kuopio, Finland
[4] Univ Pittsburgh, Dept Environm & Occupat Hlth, Pittsburgh, PA USA
关键词
sensory irritation; stereospecificity; enantiomers; alpha-pinene; beta-pinene; chirality;
D O I
10.1007/s002040050536
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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 (P degrees), all pinenes are nonreactive chemicals. For nonreactive chemicals, P degrees and olive oil-gas partition (L-Oil) 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 P degrees and L-Oil 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 similar to 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-pinenethose 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 fan 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.
引用
收藏
页码:514 / 523
页数:10
相关论文
共 61 条
[41]  
LIDE DR, 1992, CRC HDB CHEM PHYSICS
[42]   Pharmaceutical applications of cyclodextrins .1. Drug solubilization and stabilization [J].
Loftsson, T ;
Brewster, ME .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1996, 85 (10) :1017-1025
[43]  
Lu J, 1996, J APPL POLYM SCI, V61, P1011, DOI 10.1002/(SICI)1097-4628(19960808)61:6<1011::AID-APP15>3.0.CO
[44]  
2-Z
[45]   THE STEREOSPECIFIC EFFECTS OF ISOFLURANE ISOMERS IN-VIVO [J].
LYSKO, GS ;
ROBINSON, JL ;
CASTO, R ;
FERRONE, RA .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1994, 263 (1-2) :25-29
[46]   Determination of stoichiometric coefficients and apparent formation constants for alpha- and beta-CD complexes of terpenes using reversed-phase liquid chromatography [J].
Moeder, C ;
OBrien, T ;
Thompson, R ;
Bicker, G .
JOURNAL OF CHROMATOGRAPHY A, 1996, 736 (1-2) :1-9
[47]   SENSORY IRRITATION, PULMONARY IRRITATION, AND RESPIRATORY STIMULATION BY AIRBORNE BENZENE AND ALKYLBENZENES - PREDICTION OF SAFE INDUSTRIAL-EXPOSURE LEVELS AND CORRELATION WITH THEIR THERMODYNAMIC PROPERTIES [J].
NIELSEN, GD ;
ALARIE, Y .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1982, 65 (03) :459-477
[48]   MECHANISMS OF ACTIVATION OF THE SENSORY IRRITANT RECEPTOR BY AIRBORNE CHEMICALS [J].
NIELSEN, GD .
CRITICAL REVIEWS IN TOXICOLOGY, 1991, 21 (03) :183-208
[49]  
Ochocka J. R., 1996, European Journal of Pharmaceutical Sciences, V4, pS105, DOI 10.1016/S0928-0987(97)86308-7
[50]   APPROACH TO DIRECT CHIRAL RECOGNITION OF SOME TERPENIC HYDROCARBON CONSTITUENTS OF ESSENTIAL OILS BY GAS-CHROMATOGRAPHY SYSTEMS VIA ALPHA-CYCLODEXTRIN COMPLEXATION [J].
OCHOCKA, RJ ;
SYBILSKA, D ;
ASZTEMBORSKA, M ;
KOWALCZYK, J ;
GORONOWICZ, J .
JOURNAL OF CHROMATOGRAPHY, 1991, 543 (01) :171-177