title: 1H-Nuclear magnetic resonance pattern recognition studies with N-phenylanthranilic acid in the rat: time- and dose-related metabolic effects.
abstract: N-Phenylanthranilic acid (NPAA) causes renal papillary necrosis (RPN) in the rat following repeated oral dosing. Non-invasive early detection of RPN is difficult, but a number of potential biomarkers have been investigated, including phospholipid and uronic acid excretion. This study used 1H-nuclear magnetic resonance (NMR) spectroscopic analysis of urine to investigate urinary metabolic perturbations occurring in the rat following exposure to NPAA. Male Alderley Park rats received NPAA (300, 500 or 700 mg kg(-1) day(-1) orally) for 7 days, and urine was collected on days 7-8, 14-15, 21-22 and 28-29. In a separate study, urine was collected on days 1-2, 3-4, 5-6 and 7-8 from rats receiving 500 mg kg(-1) day(-1). Samples were analysed by 1H NMR spectroscopy combined with multivariate data analysis and clinical chemistry. Histopathology and clinical chemistry analysis of terminal blood samples was carried out following termination on days 4, 6, 8 and 29 (4 week time course) and days 2, 4, 6 and 8 (8 day study). Urine analysis revealed a marked, though variable, excretion of beta-hydroxybutyrate, acetoacetate and acetone (ketone bodies) seen on days 3-4, 5-6 and 7-8 of the study. It is postulated that the ketonuria might be secondary to an alteration in fatty acid metabolism due to inhibition of prostaglandin synthesis. In addition, an elevation in urinary ascorbate was observed during the first 8 days of the study. Ascorbate is considered to be a biomarker of hepatic response, probably reflecting an increased hepatic activity due to glucuronidation of NPAA.
authors.affiliation: Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, UK. becky.williams@astrazeneca.com
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Williams
authors.forename: Lisa
authors.initials: L
authors.lastname: Cottrell
authors.forename: Matthew
authors.initials: M
authors.lastname: Jacobsen
authors.forename: Lasantha R
authors.initials: LR
authors.lastname: Bandara
authors.forename: Mike D
authors.initials: MD
authors.lastname: Kelly
authors.forename: Sandy
authors.initials: S
authors.lastname: Kennedy
authors.forename: Edward A
authors.initials: EA
authors.lastname: Lock
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000652:urine; D015415:Biomarkers / Q000652:urine; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D007657:Ketone Bodies / Q000652:urine; D007681:Kidney Papillary Necrosis / Q000139:chemically induced / Q000175:diagnosis* / Q000652:urine; D008297:Male; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D016482:Urinalysis / Q000379:methods; D062367:ortho-Aminobenzoates / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D007657:Ketone Bodies; D062367:ortho-Aminobenzoates; C001209:fenamic acid; D001205:Ascorbic Acid