Absorption and dispositional kinetics of 3,3',4,4'-tetrachloroazoxybenzene and 3,3',4,4'-tetrachloroazobenzene in the male Fischer-344 rat

Persistent Link:
http://hdl.handle.net/10150/282485
Title:
Absorption and dispositional kinetics of 3,3',4,4'-tetrachloroazoxybenzene and 3,3',4,4'-tetrachloroazobenzene in the male Fischer-344 rat
Author:
Ziegler, Thomas Lynn, 1961-
Issue Date:
1997
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:
3,3',4,4'-tetrachloroazoxybenzene (TCAOB), and 3,3',4,4'-tetrachloroazobenzene (TCAOB), which are structurally similar to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are formed as byproducts during the synthesis of industrial products. They exhibit Ah receptor binding characteristics and activities similar to those defined for TCDD in vitro at equal moral doses. However, they do not express toxicities in vivo at equal molar doses. The reduced in vivo toxicity can possibly be attributed to differences in the absorption and dispositional kinetics of TCAOB and TCAB as compared to TCDD. Thus, in this study, the absorption and dispositional kinetics of TCAOB and TCAB were examined in male F-344 rats. To address this, the animals received ¹⁴C-TCAB or ¹⁴C-TCAOB and the excretion of [¹⁴C] was monitored over 96 hr. For TCAB and TCAOB, the majority of the dose was eliminated within 48 hr regardless of the route of administration. The primary route of elimination was via the feces, and significant quantities of [¹⁴C] were eliminated in the urine. Pharmacokinetic parameters indicate that the compounds are readily cleared from the blood (TCAB: t₁/₂=4 hr, CLs=12 ml/kg(min); TCAOB t1/2=7 hr, CLs=12 ml/kg(min)). By contrast, TCDD has a half-life of 16-31 days and a elimination rate of 1-2% of the [¹⁴C] -dose per day in the bile/feces with no urinary elimination. Thus, TCAOB and TCAB are eliminated faster than TCDD. Urinary metabolite analysis following administration of TCAOB or TCAB revealed a variety of dichlorolaniline conjugates, which indicates the role of azo reduction in their formation. Several metabolites were present in the bile including glucuronide conjugates of dichloroaniline (DCA) and a putative glucuronide of TCAB (formed from TCAOB as well as TCAB). Clearly, the azo bond is responsible for the enhanced elimination of TCAOB and TCAB as compared to TCDD. The removal of the intestinal flora by the antibiotic pretreatment reduced the total reductive activity but did not eliminate it completely. This indicated that the rapid metabolism and elimination of these two compounds was a result of the combination of azo-reduction by both gut flora and mammalian tissues. The production of dichloroaniline by the in vitro liver homogenate strengthens this conclusion. Since dichloroaniline was produced over time by the liver enzymes following administration of either TCAOB or TCAB, the liver thus contributes to the reduction of the azo bond.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Toxicology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology; Toxicology
Degree Grantor:
University of Arizona
Advisor:
Sipes, I. Glenn

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleAbsorption and dispositional kinetics of 3,3',4,4'-tetrachloroazoxybenzene and 3,3',4,4'-tetrachloroazobenzene in the male Fischer-344 raten_US
dc.creatorZiegler, Thomas Lynn, 1961-en_US
dc.contributor.authorZiegler, Thomas Lynn, 1961-en_US
dc.date.issued1997en_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.abstract3,3',4,4'-tetrachloroazoxybenzene (TCAOB), and 3,3',4,4'-tetrachloroazobenzene (TCAOB), which are structurally similar to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are formed as byproducts during the synthesis of industrial products. They exhibit Ah receptor binding characteristics and activities similar to those defined for TCDD in vitro at equal moral doses. However, they do not express toxicities in vivo at equal molar doses. The reduced in vivo toxicity can possibly be attributed to differences in the absorption and dispositional kinetics of TCAOB and TCAB as compared to TCDD. Thus, in this study, the absorption and dispositional kinetics of TCAOB and TCAB were examined in male F-344 rats. To address this, the animals received ¹⁴C-TCAB or ¹⁴C-TCAOB and the excretion of [¹⁴C] was monitored over 96 hr. For TCAB and TCAOB, the majority of the dose was eliminated within 48 hr regardless of the route of administration. The primary route of elimination was via the feces, and significant quantities of [¹⁴C] were eliminated in the urine. Pharmacokinetic parameters indicate that the compounds are readily cleared from the blood (TCAB: t₁/₂=4 hr, CLs=12 ml/kg(min); TCAOB t1/2=7 hr, CLs=12 ml/kg(min)). By contrast, TCDD has a half-life of 16-31 days and a elimination rate of 1-2% of the [¹⁴C] -dose per day in the bile/feces with no urinary elimination. Thus, TCAOB and TCAB are eliminated faster than TCDD. Urinary metabolite analysis following administration of TCAOB or TCAB revealed a variety of dichlorolaniline conjugates, which indicates the role of azo reduction in their formation. Several metabolites were present in the bile including glucuronide conjugates of dichloroaniline (DCA) and a putative glucuronide of TCAB (formed from TCAOB as well as TCAB). Clearly, the azo bond is responsible for the enhanced elimination of TCAOB and TCAB as compared to TCDD. The removal of the intestinal flora by the antibiotic pretreatment reduced the total reductive activity but did not eliminate it completely. This indicated that the rapid metabolism and elimination of these two compounds was a result of the combination of azo-reduction by both gut flora and mammalian tissues. The production of dichloroaniline by the in vitro liver homogenate strengthens this conclusion. Since dichloroaniline was produced over time by the liver enzymes following administration of either TCAOB or TCAB, the liver thus contributes to the reduction of the azo bond.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Toxicology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacologyen_US
thesis.degree.disciplineToxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorSipes, I. Glennen_US
dc.identifier.proquest9814364en_US
dc.identifier.bibrecord.b37741548en_US
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