title: Gender-related effects on urine L-cystine metastability.
abstract: Cystinuria is an autosomal recessive disease that causes L-cystine precipitation in urine and nephrolithiasis. Disease severity is highly variable; it is known, however, that cystinuria has a more severe course in males. The aim of this study was to compare L-cystine metastability in first-morning urine collected from 24 normal female and 24 normal male subjects. Samples were buffered at pH 5 and loaded with L-cystine (0.4 and 4 mM final concentration) to calculate the amount remaining in solution after overnight incubation at 4 °C; results were expressed as Z scores reflecting the L-cystine solubility in each sample. In addition, metabolomic analyses were performed to identify candidate compounds that influence L-cystine solubility. L-cystine solubility Z score was +0.44 ± 1.1 and -0.44 ± 0.70 in female and male samples, respectively (p < 0.001). Further analyses showed that the L-cystine solubility was independent from urine concentration but was significantly associated with low urinary excretion of inosine (p = 0.010), vanillylmandelic acid (VMA) (p = 0.015), adenosine (p = 0.029), and guanosine (p = 0.032). In vitro L-cystine precipitation assays confirmed that these molecules induce higher rates of L-cystine precipitation in comparison with their corresponding dideoxy molecules, used as controls. In silico computational and modeling analyses confirmed higher binding energy of these compounds. These data indicate that urinary excretion of nucleosides and VMA may represent important factors that modulate L-cystine solubility and may represent new targets for therapy in cystinuria.
authors: Gene Expression-Microarrays Laboratory, Bambino Gesù Children's Hospital - IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy, andrea.masotti@opbg.net.
authors: Andrea
authors: A
authors: Masotti
authors: Chiara
authors: C
authors: Laurenzi
authors: Sara
authors: S
authors: Boenzi
authors: Anna
authors: A
authors: Pastore
authors: Anna
authors: A
authors: Taranta
authors: Francesco
authors: F
authors: Bellomo
authors: Maurizio
authors: M
authors: Muraca
authors: Carlo
authors: C
authors: Dionisi-Vici
authors: Pierfrancesco
authors: P
authors: Bertucci
authors: Luca
authors: L
authors: Dello Strologo
authors: Francesco
authors: F
authors: Emma
mesh_terms: D000241:Adenosine / Q000652:urine; D000328:Adult; D011232:Chemical Precipitation; D003545:Cysteine / Q000737:chemistry / Q000652:urine*; D003555:Cystinuria / Q000652:urine; D005260:Female; D006151:Guanosine / Q000652:urine; D006801:Humans; D007288:Inosine / Q000652:urine; D008297:Male; D008875:Middle Aged; D012727:Sex Characteristics; D012995:Solubility; D014642:Vanilmandelic Acid / Q000652:urine
chemical_list: D006151:Guanosine; D014642:Vanilmandelic Acid; D007288:Inosine; D000241:Adenosine; D003545:Cysteine