Characterization of glycidol-hemoglobin adducts as biomarkers of exposure and in vivo dose

• Published in: Toxicology and applied pharmacology 2014-03, Vol.275 (3), p.213-220
• Main Authors: Honda, Hiroshi, Törnqvist, Margareta, Nishiyama, Naohiro, Kasamatsu, Toshio
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Administration, Oral; Animals; Biological and medical sciences; BIOLOGICAL MARKERS; Biomarkers - blood; CARCINOGENS; Carcinogens - administration & dosage; Carcinogens - metabolism; Carcinogens - pharmacokinetics; Carcinogens - toxicity; Dose-Response Relationship, Drug; Epoxy Compounds - administration & dosage; Epoxy Compounds - blood; Epoxy Compounds - pharmacokinetics; Epoxy Compounds - toxicity; ERYTHROCYTES; Erythrocytes - metabolism; Exposure assessment; Glycidol; HEMOGLOBIN; Hemoglobin adducts; Hemoglobins - metabolism; Humans; IN VITRO; IN VIVO; In vivo dose; ISOTHIOCYANATES; LIFE SPAN; Linear Models; Male; Medical sciences; Metabolic Clearance Rate; Models, Biological; NEOPLASMS; NUCLEAR MAGNETIC RESONANCE; Propanols - administration & dosage; Propanols - blood; Propanols - pharmacokinetics; Propanols - toxicity; QUALITY CONTROL; RATS; Rats, Sprague-Dawley; RISK ASSESSMENT; Toxicokinetics; Toxicology; VALINE; Valine - analogs & derivatives; Valine - blood; Valine - pharmacokinetics
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2014.01.010

Hemoglobin adducts have been used as biomarkers of exposure to reactive chemicals. Glycidol, an animal carcinogen, has been reported to form N-(2,3-dihydroxy-propyl)valine adducts to hemoglobin (diHOPrVal). To support the use of these adducts as markers of glycidol exposure, we investigated the kinetics of diHOPrVal formation and its elimination in vitro and in vivo. Five groups of rats were orally administered a single dose of glycidol ranging from 0 to 75mg/kg bw, and diHOPrVal levels were measured 24h after administration. A dose-dependent increase in diHOPrVal levels was observed with high linearity (R2=0.943). Blood sampling at different time points (1, 10, 20, or 40days) from four groups administered glycidol at 12mg/kg bw suggested a linear decrease in diHOPrVal levels compatible with the normal turnover of rat erythrocytes (life span, 61days), with the calculated first-order elimination rate constant (kel) indicating that the diHOPrVal adduct was chemically stable. Then, we measured the second-order rate constant (kval) for the reaction of glycidol with N-terminal valine in rat and human hemoglobin in in vitro experiments with whole blood. The kval was 6.7±1.1 and 5.6±1.3 (pmol/g globin per μMh) in rat and human blood, respectively, indicating no species differences. In vivo doses estimated from kval and diHOPrVal levels were in agreement with the area under the (concentration–time) curve values determined in our earlier toxicokinetic study in rats. Our results indicate that diHOPrVal is a useful biomarker for quantification of glycidol exposure and for risk assessment. [Display omitted] •Glycidol-hemoglobin adduct (diHOPrVal) was characterized for exposure evaluation.•We studied the kinetics of diHOPrVal formation and elimination in vitro and in vivo.•Dose dependent formation and chemical stability were confirmed in the rat study.•In vivo dose (AUC) of glycidol could be estimated from diHOPrVal levels.•diHOPrVal is considered a useful exposure and in vivo dose marker of G.