Characteristics of chemical binding to alpha 2u-globulin in vitro--evaluating structure-activity relationships

Journal Article · Thu Jan 31 23:00:00 EST 1991 · Toxicology and Applied Pharmacology; (USA)

DOI:https://doi.org/10.1016/0041-008X(91)90205-S· OSTI ID:6004129

Borghoff, S J; Miller, A B; Bowen, J P; Swenberg, J A ^[1]

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1. Chemical Industry Institute of Toxicology, Research Triangle Park, NC (USA)

alpha 2u-Globulin (alpha 2u) has been shown to accumulate in the kidneys of male rats treated with 2,2,4-trimethylpentane (TMP). 2,4,4-Trimethyl-2-pentanol (TMP-2-OH), a metabolite of TMP, is found reversibly bound to alpha 2u isolated from the kidneys of these treated rats. The objectives of the following study were to characterize the ability of (3H)TMP-2-OH to bind to alpha 2u in vitro and to determine whether other compounds that cause this protein to accumulate have the same binding characteristics. Although compounds that have been shown to cause the accumulation of alpha 2u in male rat kidneys compete in vitro with (3H)TMP-2-OH for binding to alpha 2u, they do so to varying degrees. The binding affinity (Kd) of the (3H)TMP-2-OH-alpha 2u complex was calculated to be on the order of 10(-7) M. The inhibition constant values (Ki) determined for d-limonene, 1,4-dichlorobenzene, and 2,5-dichlorophenol were all in the range 10(-4) M, whereas the Ki values for isophorone, 2,4,4- or 2,2,4-trimethyl-1-pentanol, and d-limonene oxide were determined to be in the range 10(-6) and 10(-7) M, respectively. TMP and 2,4,4- and 2,2,4-trimethylpentanoic acid did not compete for binding. This suggests that other factors, besides binding, are involved in the accumulation of alpha 2u. In this study the ability of a chemical to bind to alpha 2u was used as a measure of biological activity to assess structure-activity relationships among the chemicals tested and known to cause the accumulation of alpha 2u. The results so far suggest that binding is dependent on both hydrophobic interactions and hydrogen bonding.

• OSTI ID: 6004129
• Journal Information: Toxicology and Applied Pharmacology; (USA), Journal Name: Toxicology and Applied Pharmacology; (USA) Vol. 107:2; ISSN TXAPA; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

550501 -- Metabolism-- Tracer Techniques
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALKANES
ANIMALS
AROMATICS
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL ACCUMULATION
BODY
CHLORINATED AROMATIC HYDROCARBONS
GLOBULINS
HALOGENATED AROMATIC HYDROCARBONS
HYDROCARBONS
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
KIDNEYS
KINETICS
MAMMALS
METABOLISM
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANS
PENTANE
PROTEINS
RATS
REACTION KINETICS
RODENTS
STRUCTURE-ACTIVITY RELATIONSHIPS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES