The Utilization of Cellular and Subcellular Liver Models to Assess Glucronidation of Bisphenol A in Animals and Humans

Persistent Link:
http://hdl.handle.net/10150/193733
Title:
The Utilization of Cellular and Subcellular Liver Models to Assess Glucronidation of Bisphenol A in Animals and Humans
Author:
Kuester, Robert
Issue Date:
2006
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Bisphenol A (BPA) is a phenolic compound with industrial and commercial uses. In the liver BPA undergoes extensive metabolism and is eliminated primarily as a glucuronide conjugate. This dissertation compared the metabolism BPA in hepatocytes (HC) to those observed with hepatic microsomes (mics). These values were then scaled to predict the total hepatic metabolic clearance (CLmet ) and compared to human hepatic blood flow (HBF, 20 ml/min/kg).The mean CLint for human HC was 126±63 and 149±72 ml/min/kg for male female HC, respectively. When CLint was scaled to account for HBF, the estimated CLmet values were 16.9 and 17.3 ml/min/kg for male and female HC, respectively.To understand how age, gender, strain and species affects BPA glucuronidation, CLint of BPA was determined from incubations of mics isolated from adult male and female Sprague Dawley (SD) rats (77-day old), newborn (21- day), fetal (gestational day 19 [GD-19]) SD rats. Additional incubations were conducted with mics from adult F-344 rats, CF1 mice and humans. All specimens (HC and mics) were incubated with various concentrations of [14C]-BPA and the formation of a BPA-glucuronide (predominant metabolite) followed Michaelis Menton kinetics.Mics from adult F-344 rats formed BPA glucuronide similar those obtained from SD rats. Fetal mics showed a decreased capacity to glucuronidate BPA as compared to mics of adult rats. These data demonstrate that the glucuronsyltransferase activity responsible for BPA metabolism is developed before GD-19 and increases soon after birth. The rates of BPA-glucuronide formation (in vitro) were observed to be related to body mass with the mouse having the largest CLint and humans having the lowest.The differences in glucuronidation rates observed in vitro were minimized when values were scaled to account for the total metabolic capacity of the liver. These estimated CLmet values represent 85% to 90% of HBF which explained the very low levels of free BPA observed in the blood of human volunteers who ingested BPA (5 mg/person). Thus, hepatic glucuronidation is an efficient "first pass" mechanism which greatly reduces systemic exposure to BPA ingested orally.
Type:
text; Electronic Dissertation
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Pharmacology & Toxicology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Sipes, I. Glenn
Committee Chair:
Sipes, I. Glenn

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleThe Utilization of Cellular and Subcellular Liver Models to Assess Glucronidation of Bisphenol A in Animals and Humansen_US
dc.creatorKuester, Roberten_US
dc.contributor.authorKuester, Roberten_US
dc.date.issued2006en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractBisphenol A (BPA) is a phenolic compound with industrial and commercial uses. In the liver BPA undergoes extensive metabolism and is eliminated primarily as a glucuronide conjugate. This dissertation compared the metabolism BPA in hepatocytes (HC) to those observed with hepatic microsomes (mics). These values were then scaled to predict the total hepatic metabolic clearance (CLmet ) and compared to human hepatic blood flow (HBF, 20 ml/min/kg).The mean CLint for human HC was 126±63 and 149±72 ml/min/kg for male female HC, respectively. When CLint was scaled to account for HBF, the estimated CLmet values were 16.9 and 17.3 ml/min/kg for male and female HC, respectively.To understand how age, gender, strain and species affects BPA glucuronidation, CLint of BPA was determined from incubations of mics isolated from adult male and female Sprague Dawley (SD) rats (77-day old), newborn (21- day), fetal (gestational day 19 [GD-19]) SD rats. Additional incubations were conducted with mics from adult F-344 rats, CF1 mice and humans. All specimens (HC and mics) were incubated with various concentrations of [14C]-BPA and the formation of a BPA-glucuronide (predominant metabolite) followed Michaelis Menton kinetics.Mics from adult F-344 rats formed BPA glucuronide similar those obtained from SD rats. Fetal mics showed a decreased capacity to glucuronidate BPA as compared to mics of adult rats. These data demonstrate that the glucuronsyltransferase activity responsible for BPA metabolism is developed before GD-19 and increases soon after birth. The rates of BPA-glucuronide formation (in vitro) were observed to be related to body mass with the mouse having the largest CLint and humans having the lowest.The differences in glucuronidation rates observed in vitro were minimized when values were scaled to account for the total metabolic capacity of the liver. These estimated CLmet values represent 85% to 90% of HBF which explained the very low levels of free BPA observed in the blood of human volunteers who ingested BPA (5 mg/person). Thus, hepatic glucuronidation is an efficient "first pass" mechanism which greatly reduces systemic exposure to BPA ingested orally.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorSipes, I. Glennen_US
dc.contributor.chairSipes, I. Glennen_US
dc.contributor.committeememberHoyer, Patricia B.en_US
dc.contributor.committeememberStamer, William D.en_US
dc.contributor.committeememberMcQueen, Charlene A.en_US
dc.contributor.committeememberLantz, Cark R.en_US
dc.identifier.proquest1493en_US
dc.identifier.oclc137355814en_US
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