Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling.

Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling. Research Abstract Details 

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Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling. Abstract Text:

Carol J Belfiore,Raymond S H Yang,Laura S Chubb,Manupat Lohitnavy,Ornrat S Lohitnavy,Melvin E Andersen,

Chlordecone (CD) and mirex (M) differ by a single carbonyl group in CD in place of two chlorines in M. Although both compounds are lipophilic, their tissue distributions differ markedly: CD concentrations are highest in liver; M concentrations are highest in fat. We used tissue time course data in rats from our laboratory for CD and M and literature data from monkeys to develop PBPK models to study differences in liver and fat partitioning. The PK model for M had partitioning in tissue without specific hepatic binding. The CD model had partitioning similar to M, and also included liver binding: the maximal binding (B(max)) and binding affinity constant (Kd) required to describe the rat data were 370 nmol/g liver and 100 nM, respectively. To see if other ketones with electron withdrawing constituents at the alpha carbon were also preferentially distributed to liver, we developed a PBPK description for tissue distribution of hexafluoroacetone (HFA). Compared to acetone, HFA is known to be preferentially sequestered in liver and more slowly excreted unchanged from the body. Acetone is more equally distributed to tissues. HFA distribution was evaluated with a PBPK model that included hepatic binding. B(max) and Kd were 1.58 micromol/g liver and 301 microM. In summary, liver sequestration of CD and HFA most likely represents relatively high-affinity but reversible binding of activated carbonyls in these compounds (activated by the presence of electron withdrawing substituents on the alpha-carbons) with glutathione and glutathione transferases, that are present at much higher concentrations in liver than in other tissues. Strong, but reversible hemithioketal formation with active sulfhydryls may also be associated with the toxic responses to CD and HFA.

Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling. Publishing Authors By Initials

CJ Belfiore,RS Yang,LS Chubb,M Lohitnavy,OS Lohitnavy,ME Andersen,

For similar biochemical phenomena, metabolism, and nutrition: metabolism: pharmacokinetics: tissue distribution research abstracts see: biochemical phenomena, metabolism, and nutrition: metabolism: pharmacokinetics: tissue distribution research

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Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Toxicology

VOLUME: 234

Page Numbers: 59-72

Journal Abbreviation:

ISSN: 0300-483X

DAY: 17

MONTH: 02

YEAR: 2007

Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 361055

Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling. Keywords Mesh Terms:

KEYWORDS: Tissue Distribution

MESH TERMS: pharmacokinetics

Chemical & Substance for Abstract: Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling. Information

Substance Name: hexafluoroacetone

Registry Number: 684-16-2

Grant and Affiliation Information for Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling.

AFFILIATION: Quantitative and Computational Toxicology Group, Department of Environmental and Radiological Health Sciences, Colorado State University, Ft Collins, CO 80523, USA. carol.belfiore@comcast.net

Country: Ireland

AGENCY: United States NIEHS

GRANT: T32 ES07321

ACRONYM: ES

MEDLINETA: Toxicology

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