THE IN VITRO METABOLISM OF POLYCHLORINATED BIPHENYLS: SPECIES VARIATION.

Persistent Link:
http://hdl.handle.net/10150/187660
Title:
THE IN VITRO METABOLISM OF POLYCHLORINATED BIPHENYLS: SPECIES VARIATION.
Author:
SCHNELLMANN, RICKY GENE.
Issue Date:
1984
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:
Polychlorinated biphenyls (PCBs) are ubiquitious environmental pollutants that cause a number of diverse toxicities. The chemical stability of PCBs is responsible for their persistence in the environment, while their lipid solubility and resistance to biotransformation results in their accumulation in a number of animal species. The rate of PCB elimination is dependent on the ability of each animal species to metabolize a particular PCB congener. The goal of this project was to determine if in vitro liver microsomal metabolism studies could predict in vivo metabolism and to examine the reasons for the species variation in PCB metabolism. Kinetic constants were developed from in vitro metabolism studies using 4,4'-dichlorobiphenyl (4-DCB), 2,2',3,3',6,6'-hexachlorobiphenyl (236-HCB) and 2,2',4,4',5,5'-hexachlorobiphenyl (245-HCB) and liver microsomes from the human, dog, monkey and rat. An excellent correlation between the in vitro Vmax values and the in vivo hepatic clearance values was obtained. Human microsomal PCB metabolism was most similar to the rat. The in vitro human results were consistent with available in vivo data. All species produced the same major metabolites. The major metabolite of 4-DCB was 4,4'-dichloro-3-biphenylol and the two major metabolites of 236-HCB were 2,2',3,3',6,6'-hexachloro-4-biphenylol and 2,2',3,3',6,6'-hexachloro-5-biphenylol. The dog was the only species found to metabolize 245-HCB in vitro. Metabolites of 245-HCB were not identified. Studies of metabolism, covalent binding of PCB-equivalents to microsomal protein and metabolites demonstrated that the dog can metabolize PCBs more readily than other species because the dog has an alternate pathway of PCB metabolism. This pathway is either not found in other species or only found to a limited extent. Furthermore, an arene oxide does not seem to be involved in this alternative pathway. In summary, for certain classes of compounds in vitro to in vivo extrapolation is possible and may prove to be very useful in predicting the appropriate animal model for humans. Secondly, the dog appears to be quite different in its metabolism of PCBs in that it may have an alternate route of metabolism not involving an arene oxide.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Polychlorinated biphenyls -- Metabolism.; Liver cells -- Physiology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology and Toxicology; Graduate College
Degree Grantor:
University of Arizona

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleTHE IN VITRO METABOLISM OF POLYCHLORINATED BIPHENYLS: SPECIES VARIATION.en_US
dc.creatorSCHNELLMANN, RICKY GENE.en_US
dc.contributor.authorSCHNELLMANN, RICKY GENE.en_US
dc.date.issued1984en_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.abstractPolychlorinated biphenyls (PCBs) are ubiquitious environmental pollutants that cause a number of diverse toxicities. The chemical stability of PCBs is responsible for their persistence in the environment, while their lipid solubility and resistance to biotransformation results in their accumulation in a number of animal species. The rate of PCB elimination is dependent on the ability of each animal species to metabolize a particular PCB congener. The goal of this project was to determine if in vitro liver microsomal metabolism studies could predict in vivo metabolism and to examine the reasons for the species variation in PCB metabolism. Kinetic constants were developed from in vitro metabolism studies using 4,4'-dichlorobiphenyl (4-DCB), 2,2',3,3',6,6'-hexachlorobiphenyl (236-HCB) and 2,2',4,4',5,5'-hexachlorobiphenyl (245-HCB) and liver microsomes from the human, dog, monkey and rat. An excellent correlation between the in vitro Vmax values and the in vivo hepatic clearance values was obtained. Human microsomal PCB metabolism was most similar to the rat. The in vitro human results were consistent with available in vivo data. All species produced the same major metabolites. The major metabolite of 4-DCB was 4,4'-dichloro-3-biphenylol and the two major metabolites of 236-HCB were 2,2',3,3',6,6'-hexachloro-4-biphenylol and 2,2',3,3',6,6'-hexachloro-5-biphenylol. The dog was the only species found to metabolize 245-HCB in vitro. Metabolites of 245-HCB were not identified. Studies of metabolism, covalent binding of PCB-equivalents to microsomal protein and metabolites demonstrated that the dog can metabolize PCBs more readily than other species because the dog has an alternate pathway of PCB metabolism. This pathway is either not found in other species or only found to a limited extent. Furthermore, an arene oxide does not seem to be involved in this alternative pathway. In summary, for certain classes of compounds in vitro to in vivo extrapolation is possible and may prove to be very useful in predicting the appropriate animal model for humans. Secondly, the dog appears to be quite different in its metabolism of PCBs in that it may have an alternate route of metabolism not involving an arene oxide.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectPolychlorinated biphenyls -- Metabolism.en_US
dc.subjectLiver cells -- Physiology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.identifier.proquest8412676en_US
dc.identifier.oclc690934629en_US
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