Abstract
A method is described that allows noninvasive identification and quantitative assessment of lipid classes present in sebaceous excretions in rodents. The method relies on direct high-field proton NMR analysis of common group lipid protons in deuterated organic solvent extracts of fur. Extracts from as little as 15 mg of fur from rat, mouse, and hamster provided acceptable results on a 600 MHz NMR equipped with a cryogenically cooled proton-observe probe. In rats, sex- and age-related differences in lipid composition are larger than differences in fur collected from various body regions within an individual and much larger than interanimal differences in age- and sex-matched specimens. The utility of this method to noninvasively monitor drug-induced sebaceous gland atrophy in rodents is demonstrated in rats dosed with a stearoyl-CoA desaturase 1 (SCD1) inhibitor. In this model, a 35% reduction in sebum lipids, extracted from fur, was observed. Finally, structural elucidation of cholesta-7,24-dien-3β-ol ester as the most prominent, previously unidentified sebum sterol ester in male Syrian hamsters is described. The utility of this method for drug and cosmetic safety and efficacy assessment is discussed.
Highlights
Supplementary key words metabolomics skin lipid fur sebum fur lipid sebum lipid human sebum rat sebum mouse sebum hamster sebum NMR assay lipid class measurement stearoyl-CoA desaturase 1
These were identified by comparison with literature values as well as by comparison with spectra from, or addition of, authentic reference standards for at least one member of each class of lipid measured in this study
In order to assign peaks in the 4.5–4.8 ppm region, which contains the methine proton from the 3 position of esterified sterols, the NMR spectra of synthetic stearoyl lathosterol ester (LE) and cholesteryl ester (CE) were recorded and compared with fur extract NMR spectra (Fig. 2)
Summary
Many analytical methods for sebum assessment have been reported These can be divided into two groups based on whether they 1) distinguish individual lipid molecules or 2) measure lipid classes independent of the exact FA substituents. The NMR method relies on accurate integration of specific protons on selected analytes in extracts of skin biopsies and absorbent films commonly used in clinical evaluation of sebum excretion. We apply the method to study fur lipid changes in rodents upon dosing with the previously reported stearoyl-CoA desaturase 1 (SCD1) inhibitor, compound 1 [10], as shown in Scheme 1. We demonstrate a significant reduction of fur lipids upon treatment of rats and hamsters with compound 1, a compound known to cause alopecia and atrophy of sebaceous glands in mice [8].
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