Correspondence Comment on “Stereoselective Degradation Kinetics of Theta-Cypermethrin in Rats” We herein refer to a recent article published in Environmental Science and Technology entitled “Stereoselective degradation kinetics of theta-cypermethrin in rats” by Wang et al. (1). Among others, an in vivo unidirectional chiral inversion of (+)-theta-cypermethrin to (-)-theta-cypermethrin, as analyzed by a stereoselective analytical HPLCDAD assay was claimed. As interested yet critical readers of the article, we must raise serious doubts on the appropriateness and validity of the interpretations of the experimental data. Cypermethrin, R-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane carboxylate, is a type II pyrethroid insecticide and contains three stereogenic centers (Figure 1). Hence, eight stereoisomers or four enantiomeric pairs do exist. Theta-cypermethrin represents the racemic mixture of the (-)-(RR,1S,3R) and (+)-(RS,1R,3S) enantiomers. On the basis of the appearance of a peak at the elution time of (-)-theta-cypermethrin in the chromatogram of rat plasma samples collected 1 min after iv administration of (+)-theta-cypermethrin chiral bioinversion was postulated and no attempts were undertaken to verify this surprising finding by complementary methods. Simultaneous inversion of all three stereoconfigurations is, however, most unlikely from chemical and biochemical points of view. A probability tree makes evident that for spontaneous chemical interconversion of (+)-theta-cypermethrin into its (-)-enantiomer the most likely mechanism is supposed to be a three-step epimerization procedure (Figure 1). The stereocenter of the R-benzylic carbon atom is susceptible to stereointerconversion (epimerization) already in aqueous media (2). Inversion of this configuration in (+)theta-cypermethrin yields the (RR,1R,3S)-stereoisomer (first epimerization step). To end up with the (-)-theta-cypermethrin enantiomer two more epimerization steps are required, which are, however, expected to proceed with lower probability, in particular regarding inversion at the C3configuration. As a second mechanism, inversion may be mediated enzymatically as, for example, known for the unidirectional interconversion of the single-stereocenter of profens (3). A simultaneous enzymatic inversion of the three stereocenters of (+)-theta-cypermethrin is, however, hardly conceivable and, as for the chemical pathway, epimer or diastereomer mixture formation, respectively, is assumed to occur with higher probability than enantiomer formation. Under the employed separation conditions a baseline separation of theta-cypermethrin enantiomers (R ) 1.31, RS ) 2.01) but not of all eight cypermethrin stereoisomers had been possible (4). For example, the (RR,1R,3S)-stereoisomer tended to coelute with the (RR,1S,3R)-stereoisomer which is actually the (-)-theta-cypermethrin enantiomer (5). As this limited diastereoselectivity was not considered as a potential source for false conclusions by the authors a bioinversion of (+)-theta-cypermethrin cannot be postulated. Another explanation, also not taken into account by the authors, might be invoked to explain the appearance of a peak at the elution time of (-)-theta-cypermethrin. Like other pyrethroids, theta-cypermethrin may be rapidly metabolized 7950
9
ENVIRONMENTAL SCIENCE & TECHNOLOGY / VOL. 40, NO. 24, 2006
FIGURE 1. Chemical structure of cypermethrin and probability tree for interconversion of (+)-theta-cypermethrin to (-)-theta-cypermethrin (arrows indicate inverted stereocenter). in plasma by the action of esterases which cause an ester bond cleavage and formation of characteristic metabolites. This degradation process may even occur in significant extent during sample storage if no esterase inhibitors are added (6). It has not been convincingly shown by appropriate validation measures that cypermethrin metabolites do not coelute and interfere with the parent theta-cypermethrin enantiomer peaks and accordingly valid conclusions cannot be proposed. In summary, the employed analytical approach is, in our opinion, lacking proper chromatographic selectivity to allow postulation of in vivo unidirectional bioinversion of (+)theta-cypermethrin on a sound scientific basis. As long as other more plausible explanations like the ones given above are not considered such a statement is invalid and bare of fundamental proof. Along this line, it also has to be questioned how the stereochemical integrity of the single theta-cypermethrin enantiomers in the aqueous solutions prior to administration as well as in plasma and tissues during storage and sample preparation was controlled. Ex vivo conversion of theta-cypermethrin (both chiral inversion and ester cleavage) might pretend stereochemical phenomena such as claimed. The findings of the commented article of stereoselective toxicokinetic effects of theta-cypermethrin should, hence, be taken with care, especially if these data are intended to be used for hazard/risk assessment purposes. Instead, we call outmost attention to the use of appropriately validated analytical methods, not forgetting assay selectivity (achiral/chiral) as the most critical parameter if the identity is playing a decisive role for the interpretation of the results. This technical know-how on the proper use of analytical tools ultimately constitutes the core feature of reliable toxicological studies and interpretations deduced thereof. 10.1021/es062454n CCC: $33.50
2006 American Chemical Society Published on Web 11/16/2006
Literature Cited (1) Wang, Q.; Qiu, J.; Zhu, W.; Jia, G.; Li, J.; Bi, C.; Zhou, Z. Stereoselective degradation kinetics of theta-cypermethrin in rats. Environ. Sci. Technol. 2006, 40, 721-726. (2) Liu, W.; Qin, S.; Gan, J. Chiral stability of synthetic pyrethroid insecticides. J. Agric. Food Chem. 2005, 53, 38143820. (3) Wso´l, V.; Ska´lova´, L.; Szota´kova´, B. Chiral inversion of drugs: Coincidence or principle? Curr. Drug Metab. 2004, 5, 517533. (4) Wang, P.; Zhou, Z.; Jiang, S.; Yang, L. Chiral resolution of cypermethrin on cellulose-tris(3,5-dimethylphenylcarbamate) chiral stationary phase. Chromatographia 2004, 59, 625-629. (5) Edwards, D. P.; Ford, M. G. Separation and analysis of the diastereomers and enantiomers of cypermethrin and related compounds. J. Chromatogr., A 1997, 777, 363369. (6) Leng, G.; Ku ¨ hn, K. H.; Idel, H. Biological monitoring of pyrethroids in blood and pyrethroid metabolites in urine: applications and limitations. Sci. Total Environ. 1997, 199, 173-181.
Wolfgang Bicker,* Michael La1 mmerhofer, and Wolfgang Lindner Christian Doppler Laboratory for Molecular Recognition Materials Department of Analytical and Food Chemistry University of Vienna Wa¨hringer Strasse 38 A-1090 Vienna, Austria
Wolfgang Bicker Center for Analytical Chemistry Department for Agrobiotechnology - IFA-Tulln University of Natural Resources and Applied Life Sciences Konrad-Lorenz-Strasse 20 A-3430 Tulln, Austria ES062454N
VOL. 40, NO. 24, 2006 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
9
7951
