Biological fate of styrene oxide adducts with globin: Elimination of cleavage products in the rat urine

• Published in: Toxicology letters 2016-11, Vol.261, p.26-31
• Main Authors: Mráz, Jaroslav, Hanzlíková, Iveta, Dušková, Šárka, Dabrowská, Ludmila, Chrástecká, Hana, Vajtrová, Radka, Linhart, Igor
• Format: Article
• Language: English
• Subjects: Adducts; Animals; Biological monitoring; Biomarkers - metabolism; Biomarkers - urine; Cleavage; Conjugation; Environmental Monitoring; Environmental Pollutants - chemistry; Environmental Pollutants - metabolism; Environmental Pollutants - urine; Epoxy Compounds - chemistry; Epoxy Compounds - metabolism; Erythrocytes; Globin adducts; Globins - metabolism; Globins - urine; Glutathione; Hydrolysis; Hydroxy(phenyl)ethyl mercapturic acids; Life span; Male; Rats; Rats, Wistar; Styrene oxide; Styrenes; Urinary adducts; Urine; Xenobiotics
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2016.08.022

•Styrene oxide produces covalent adducts at some amino acids in rat globin in vivo.•On hydrolytic cleavage of globin these amino acid adducts are eliminated in urine.•Excretion kinetics of the urinary adducts reflects the erythrocyte life span. The in vivo fate of globin adducts with styrene 7,8-oxide (SO), an electrophilic metabolic intermediate of styrene, was studied in male Wistar rats dosed intraperitoneally with racemic SO, 100mg/kg b.w. Regioisomeric hydroxy(phenyl)ethyl (HPE) adducts at Cys, N-terminal Val, Lys and His in globin were determined and their elimination from blood was followed during 60days, corresponding to life span of rat erythrocytes. In the rat urine, Nα-acetylated products of hydrolytic cleavage of the HPE adducts with Cys, Lys and His were determined. On the first day post-exposure, abundant Nα-acetyl-HPE-Cys adducts (mercapturic acids) formed via direct conjugation of SO with hepatic glutathione were excreted rapidly, but then a much slower phase of elimination reflecting formation of Nα-acetyl-HPE-Cys via cleavage of the adducted globin was observed. A two-phase elimination occurred also in urinary Nα-acetyl-HPE adducts with His and Lys. While a decline by 75–85% during the first 7days post-exposure most likely reflected elimination of adducted albumin, the subsequent slow decline until day 60 corresponded to elimination kinetics of the adducted globin. Thus, the study not only provided original data on the fate of SO-globin adducts but also allowed to reveal general toxicokinetics properties of the urinary cleavage products as a novel type of chemical exposure biomarkers.