Disposition and metabolism of 4-vinyl-1-cyclohexene diepoxide in female Fischer 344 rats and B6C3F(1) mice.

Persistent Link:
http://hdl.handle.net/10150/187076
Title:
Disposition and metabolism of 4-vinyl-1-cyclohexene diepoxide in female Fischer 344 rats and B6C3F(1) mice.
Author:
Salyers, Kevin Lyndon.
Issue Date:
1995
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:
4-Vinyl-1-cyclohexene diepoxide (VCD) is a known carcinogen, a direct acting mutagen, and an ovarian toxicant. Female B6C3F₁ mice are more susceptible to the ovarian toxicity of VCD than female Fischer 344 rats, a difference which may be explained by the disposition/metabolism of VCD. Following a single dose ¹⁴C-VCD was rapidly metabolized and excreted predominantly in the urine of both species. However, the excretion rate was higher in the female rats compared to female mice. The major metabolite present in rat urine was the 4-(1,2-dihydroxy) ethyl-1,2-dihydroxycyclohexane (tetrol). However, in the mouse, the tetrol was only a minor metabolite. The major metabolites appeared to be polar conjugates of VCD, which also appeared in rat urine. This difference in urinary metabolites indicates different metabolic pathways of VCD between the two species. The rat hydrolyzes VCD by epoxide hydrolase to form the tetrol and also conjugates VCD. The mouse conjugates VCD but has a reduced capacity to hydrolyze the epoxide moieties. To further characterize the disposition of VCD, blood kinetic parameters were investigated. Although both species rapidly cleared VCD from the plasma, the mouse had a shorter plasma t(1/2) and mean residence time (MRT). The volume of distribution was also five fold greater in the mouse compared to the rat. Therefore, VCD distributes from the plasma to tissues, possibly target tissues (ie. ovaries), more profoundly in the mouse than in the rat. In vitro metabolism studies were performed to determine if differences in epoxide hydrolase explain the inability of the mouse to excrete the tetrol metabolites. Although the K(m) was similar, the V(max) for conversion of VCD to the tetrol was four-fold higher in rat hepatic microsomes compared to those of the mouse. Therefore, differences in the disposition and metabolism of VCD exist between female Fischer 344 rats and B6C3F₁ mice. These differences explain, in part, the increased susceptibility of the mouse ovary to the toxic effects of VCD.
Type:
text; Dissertation-Reproduction (electronic)
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology and Toxicology; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Sipes, I. Glenn

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleDisposition and metabolism of 4-vinyl-1-cyclohexene diepoxide in female Fischer 344 rats and B6C3F(1) mice.en_US
dc.creatorSalyers, Kevin Lyndon.en_US
dc.contributor.authorSalyers, Kevin Lyndon.en_US
dc.date.issued1995en_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.abstract4-Vinyl-1-cyclohexene diepoxide (VCD) is a known carcinogen, a direct acting mutagen, and an ovarian toxicant. Female B6C3F₁ mice are more susceptible to the ovarian toxicity of VCD than female Fischer 344 rats, a difference which may be explained by the disposition/metabolism of VCD. Following a single dose ¹⁴C-VCD was rapidly metabolized and excreted predominantly in the urine of both species. However, the excretion rate was higher in the female rats compared to female mice. The major metabolite present in rat urine was the 4-(1,2-dihydroxy) ethyl-1,2-dihydroxycyclohexane (tetrol). However, in the mouse, the tetrol was only a minor metabolite. The major metabolites appeared to be polar conjugates of VCD, which also appeared in rat urine. This difference in urinary metabolites indicates different metabolic pathways of VCD between the two species. The rat hydrolyzes VCD by epoxide hydrolase to form the tetrol and also conjugates VCD. The mouse conjugates VCD but has a reduced capacity to hydrolyze the epoxide moieties. To further characterize the disposition of VCD, blood kinetic parameters were investigated. Although both species rapidly cleared VCD from the plasma, the mouse had a shorter plasma t(1/2) and mean residence time (MRT). The volume of distribution was also five fold greater in the mouse compared to the rat. Therefore, VCD distributes from the plasma to tissues, possibly target tissues (ie. ovaries), more profoundly in the mouse than in the rat. In vitro metabolism studies were performed to determine if differences in epoxide hydrolase explain the inability of the mouse to excrete the tetrol metabolites. Although the K(m) was similar, the V(max) for conversion of VCD to the tetrol was four-fold higher in rat hepatic microsomes compared to those of the mouse. Therefore, differences in the disposition and metabolism of VCD exist between female Fischer 344 rats and B6C3F₁ mice. These differences explain, in part, the increased susceptibility of the mouse ovary to the toxic effects of VCD.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)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.contributor.chairSipes, I. Glennen_US
dc.contributor.committeememberBrendel, Klausen_US
dc.contributor.committeememberConsroe, Paulen_US
dc.contributor.committeememberHoyer, Patriciaen_US
dc.contributor.committeememberMacKenzie, Neilen_US
dc.identifier.proquest9531098en_US
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