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The present study describes for the first time, a metabolic profile reflecting the osteoporosis progression in 364 pre- and postmenopausal Chinese women using GC-MS. In order to accurately evaluate the dynamic changes of metabolites along with estrogen deficiency and osteoporosis progression, we divided these subjects into the following four groups: premenopausal women with normal bone mass density (BMD, group I), postmenopausal women with normal BMD (group II), postmenopausal women with osteopenia (group III) and postmenopausal women with osteoporosis (group IV), according to their menopause or low BMD status. Principal component analysis (PCA) and Partial least squares-discriminant analysis (PLS-DA) were used to evaluate the associations of metabolic changes with low BMD or estrogen deficiency. Twelve metabolites identified by the PLS-DA model were found to be able to differentiate low BMD groups from normal BMD groups. Of the 12 metabolites, five free fatty acids (LA, oleic acid, AA and 11,14-eicosadienoic acid) have the most potential to be used as osteoporosis biomarkers due to their better correlations with BMD, and high sensitivity and specificity in distinguishing the low BMD groups from the normal BMD groups calculated by the receiver operating characteristic curve (ROC). The lipid profile may be useful for osteoporosis prediction and diagnosis.

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1. A comprehensive method for the simultaneous characterization of xenobiotic compound inhibition of nine major CYP enzymes in human liver microsomes was established by using 16 CYP-catalyzed reactions of 14 probe substrates with three cocktail incubation sets and a single LC/MS/MS analysis. 2. The three cocktail subgroups were developed to minimize the effects of organic solvents, polyunsaturated fatty acids and mutual substrate interactions: Group I was composed of tolbutamide (CYP2C9), S-mephenytoin (CYP2C19), testosterone (CYP3A4), dextromethorphan (CYP2D6); Group II was composed of nifedipine (CYP3A4), midazolam (CYP3A4), coumarin (CYP2A6), bupropion (CYP2B6), diclofenac (CYP2C9); Group III was composed of phenacetin (CYP1A2), chlorzoxazone (CYP2E1), omeprazole (CYP2C19 and CYP3A4), paclitaxel (CYP2C8), (+)-bufuralol (CYP2D6). In the case of CYP2C9, CYP2C19, CYP2D6 and CYP3A4, multiple probe substrates were used due to the phenomenon of multiple substrate-binding pockets and substrate-dependent inhibition. All probe metabolites were simultaneously analyzed with a polarity switching mode in a single LC/MS/MS run. 3. This method was validated against the single probe substrate assay using 12 well-characterized CYP inhibitors and two new entities (GT0918, MDV3100). The IC50 values of each inhibitor in the cocktail agreed well with that of the individual probe drug as well as with values reported in previous literatures.

The mechanism of asthenozoospermia remains unclear. The knowledge of the metabolism of fatty acids in seminal plasma is important and meaningful for the pathological study of asthenozoospermia. We present an optimised assay of extraction and derivatisation followed by GC/MS to analyse metabolites, especially fatty acids, in seminal plasma from healthy and asthenozoospermic men. Eighty-nine peaks including 17 kinds of fatty acids were analysed and identified in the chromatogram. The GC/MS data were analysed using t test, fold change and partial least squares discriminant analysis to explore the potential biomarkers of asthenozoospermia. Seven metabolites in asthenozoospermic group were found to be significantly different from those in the normal group (with p < .05, fold change >1.2 and variable importance for projection >1). Of which, high levels of oleic acid and palmitic acid in seminal plasma from asthenozoospermic men may indicate a membrane metabolism disorder in spermatozoa and the lack of valine in the asthenozoospermic group may contribute to poor sperm motility. The results may facilitate the understanding of the role of fatty acids and amino acids in asthenozoospermia and provide solid foundation for further pathological study of asthenozoospermia.

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Based on the GC-MS metabolomic platform, four typical pathological phases during the progression of postmenopausal osteoporosis were described. Several differentiating metabolites and metabolic pathways were found to be closely related to the pathology of postmenopausal osteoporosis. Our results provided a solid foundation for further studies on early diagnosis and pathomechanistic evaluation.