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In vitro uptake of methyl tert-butyl ether in male rat kidney: use of a two-compartment model to describe protein interactions.
Toxicol Appl Pharmacol. 1997 Aug; 145(2):340-8.TA

Abstract

Methyl tert-butyl ether (MTBE) is a gasoline additive that causes renal tumors in male rats. In the process of measuring chemical specific parameters necessary to develop a quantitative dosimetry model of MTBE in rats, the uptake of MTBE was found to be 5.5 times greater in male than in female F-344 rat kidney homogenate. The objectives of this study were to characterize the factor(s) that influences the high uptake of MTBE into male rat kidney in vitro and to develop a system to evaluate the interaction of MTBE with the male rat-specific protein, alpha 2u-globulin (alpha 2u). The uptake of MTBE in male, but not female, rat kidney homogenate was found to be dependent on protein and chemical concentrations. When [14C]MTBE was incubated with male rat kidney homogenate, radioactivity coeluted with the total protein fraction on a gel filtration column. An interaction between [14C]MTBE and male rat kidney proteins was not found under conditions of dialysis or anion exchange chromatography. A two-compartment vial equilibration model was used to assess the interaction between MTBE and alpha 2u. Using this system, the dissociation constant for MTBE and alpha 2u was estimated to be 2.15 x 10(-4) M, which is in the range of other chemicals known to bind to alpha 2u and cause alpha 2u-mediated nephropathy. d-Limonene oxide was used to validate this two-compartment vial equilibration system. These findings illustrate a technique useful in estimating the dissociation constant for a volatile chemical and a protein, as well as explain the process that contributes to the uptake of MTBE into male rat kidney homogenate in vitro. A description of the weak interaction between MTBE and alpha 2u will be used to refine a physiologically based pharmacokinetic model to describe the target tissue (kidney) concentrations of MTBE.

Authors+Show Affiliations

Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9266807

Citation

Poet, T S., and S J. Borghoff. "In Vitro Uptake of Methyl Tert-butyl Ether in Male Rat Kidney: Use of a Two-compartment Model to Describe Protein Interactions." Toxicology and Applied Pharmacology, vol. 145, no. 2, 1997, pp. 340-8.
Poet TS, Borghoff SJ. In vitro uptake of methyl tert-butyl ether in male rat kidney: use of a two-compartment model to describe protein interactions. Toxicol Appl Pharmacol. 1997;145(2):340-8.
Poet, T. S., & Borghoff, S. J. (1997). In vitro uptake of methyl tert-butyl ether in male rat kidney: use of a two-compartment model to describe protein interactions. Toxicology and Applied Pharmacology, 145(2), 340-8.
Poet TS, Borghoff SJ. In Vitro Uptake of Methyl Tert-butyl Ether in Male Rat Kidney: Use of a Two-compartment Model to Describe Protein Interactions. Toxicol Appl Pharmacol. 1997;145(2):340-8. PubMed PMID: 9266807.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro uptake of methyl tert-butyl ether in male rat kidney: use of a two-compartment model to describe protein interactions. AU - Poet,T S, AU - Borghoff,S J, PY - 1997/8/1/pubmed PY - 1997/8/1/medline PY - 1997/8/1/entrez SP - 340 EP - 8 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 145 IS - 2 N2 - Methyl tert-butyl ether (MTBE) is a gasoline additive that causes renal tumors in male rats. In the process of measuring chemical specific parameters necessary to develop a quantitative dosimetry model of MTBE in rats, the uptake of MTBE was found to be 5.5 times greater in male than in female F-344 rat kidney homogenate. The objectives of this study were to characterize the factor(s) that influences the high uptake of MTBE into male rat kidney in vitro and to develop a system to evaluate the interaction of MTBE with the male rat-specific protein, alpha 2u-globulin (alpha 2u). The uptake of MTBE in male, but not female, rat kidney homogenate was found to be dependent on protein and chemical concentrations. When [14C]MTBE was incubated with male rat kidney homogenate, radioactivity coeluted with the total protein fraction on a gel filtration column. An interaction between [14C]MTBE and male rat kidney proteins was not found under conditions of dialysis or anion exchange chromatography. A two-compartment vial equilibration model was used to assess the interaction between MTBE and alpha 2u. Using this system, the dissociation constant for MTBE and alpha 2u was estimated to be 2.15 x 10(-4) M, which is in the range of other chemicals known to bind to alpha 2u and cause alpha 2u-mediated nephropathy. d-Limonene oxide was used to validate this two-compartment vial equilibration system. These findings illustrate a technique useful in estimating the dissociation constant for a volatile chemical and a protein, as well as explain the process that contributes to the uptake of MTBE into male rat kidney homogenate in vitro. A description of the weak interaction between MTBE and alpha 2u will be used to refine a physiologically based pharmacokinetic model to describe the target tissue (kidney) concentrations of MTBE. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/9266807/In_vitro_uptake_of_methyl_tert_butyl_ether_in_male_rat_kidney:_use_of_a_two_compartment_model_to_describe_protein_interactions_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(97)98193-X DB - PRIME DP - Unbound Medicine ER -