On the structure-activity relationships and mechanism of organotin induced, nonenergy dependent swelling of liver mitochondria

Wulf, Richard G.; Byington, Keith H.

doi:10.1016/0003-9861(75)90454-3

Cited by 61 publications

(19 citation statements)

References 21 publications

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“…The method used to arrive at ClogP is described elsewhere (10). It should be noted that for the tri-n-alkyltin compounds tested there is good agreement between ClogP and experimentally determined values (see Table 5) (17).…”

Section: Methodsmentioning

confidence: 98%

Chemical Specificity of the PDR5 Multidrug Resistance Gene Product of Saccharomyces cerevisiae Based on Studies with Tri- n -Alkyltin Chlorides

Golin¹,

Barkatt²,

Cronin

et al. 2000

Antimicrob Agents Chemother

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To understand the chemical basis of action for the PDR5-encoded multidrug resistance transporter of Saccharomyces cerevisiae, we compared the relative hypersensitivities of the wild-type (RW2802) and null mutant strains toward a series of tri-n-alkyltin compounds. These compounds differ from each other in a systematic fashion-either by hydrocarbon chain length or by anion composition. Using zone-of-inhibition and fixed-concentration assays, we found that the ethyl, propyl, and butyl compounds are strong PDR5 substrates, whereas the methyl and pentyl compounds are weak. We conclude that hydrophobicity and anion makeup are relatively unimportant factors in determining whether a tri-n-alkyltin compound is a good PDR5 substrate but that the dissociation of the compound and the molecular size are significant.The yeast PDR5 gene encodes a 160-kDa protein that is a member of the ATP-binding cassette transport superfamily (1). Loss-of-function mutations in this gene create broad-spectrum hypersensitivity to a large array of chemically diverse inhibitors because of an inability to cause efflux of such compounds (11). Overexpression of the PDR5 gene product, in contrast, results in multidrug resistance (MDR) (1,14). As is the case for most of the other MDR proteins encountered in eucaryotes, the chemical basis for the broad specificities of the PDR5 transporter remains unknown. Precise knowledge of the mechanism by which transporters recognize their substrates might have important clinical ramifications. Furthermore, it could help explain the basis for the interesting classes of MDR mutants with altered specificities that have been identified for yeast (3) and mammalian (6, 12) cells.Most models of MDR action invoke the requirement of hydrophobicity (5). This idea is based upon the fact that several structurally related drugs that differ in their ability to be transported by the mammalian MDR transporter differ in their relative hydrophobicities, as measured by their water/octanol partitioning ratio (logP) (15,18). This observation was used as evidence for proposing that the mammalian MDR protein is a flippase. Thus, a drug must be intercalated into the lipid bilayer before it interacts with a binding site on the efflux protein (5).To address various models of PDR5 substrate recognition, we analyzed the abilities of the wild-type and isogenic null mutant proteins to mediate resistance toward a family of structurally related tri-n-alkyltin compounds that interfere with mitochondrial ATPase activity (2) and differ systematically either by the length of the hydrocarbon chain or by the counterion. Zoneof-inhibition and fixed-concentration assays were used so that quantitative comparisons could be made with a high degree of accuracy. The results obtained were compared to measures of hydrophobicity, ion dissociation, and molecular size. MATERIALS AND METHODSYeast strains. The two isogenic strains of Saccharomyces cerevisiae used in this study were previously described (11). RW2802 contains a functional PDR5 gene, while JG436 ha...

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Section: Methodsmentioning

confidence: 98%

Chemical Specificity of the PDR5 Multidrug Resistance Gene Product of Saccharomyces cerevisiae Based on Studies with Tri- n -Alkyltin Chlorides

Golin¹,

Barkatt²,

Cronin

et al. 2000

Antimicrob Agents Chemother

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“…[9][10][11] The toxic properties of organotin compounds depend on the biological object and on the chemical structure of the compounds. [12][13][14] Toxicity of trialkyltin compounds has been confirmed in the case of mammals and algae, [15][16][17] for instance. Since these compounds are soluble in organic solvents, this property could lead to the hypothesis that the primary step in organotin action could be solubilization in the phospholipid bilayer.…”

Section: Introductionmentioning

confidence: 90%

A Synergistic Effect of Select Organotin Compounds and Ionic Surfactants on Liposome Membranes

Kuczera

Gabrielska

Kral

et al. 1997

Appl. Organometal. Chem.

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“…Laughlin et al (1986b) suggested that small quantities of mono-or dibutyltin contamination might be responsible for the wide range of values reported, but other factors may also influence the value measured such as chemical speciation ofTBT cation with OHI-, CP-, or COl- (Laughlin et al, 1986b) or measurement technique. Tsuda et al (1988a) found that Wulf and Byington, 1975 Derivatization with n-pentylmagnesium bromide, gas chromatography with modified flame photometric detector. TBTCI 1300 Total tin in octanol phase measured, aqueous TBTO 5500 7000…”

Section: The Wide Range Of Bioaccumulation Factor Valuesmentioning

confidence: 99%

Bioaccumulation of TBT by Aquatic Organisms

Laughlin¹

1996

Organotin

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On the structure-activity relationships and mechanism of organotin induced, nonenergy dependent swelling of liver mitochondria

Cited by 61 publications

References 21 publications

Chemical Specificity of the PDR5 Multidrug Resistance Gene Product of Saccharomyces cerevisiae Based on Studies with Tri- n -Alkyltin Chlorides

Chemical Specificity of the PDR5 Multidrug Resistance Gene Product of Saccharomyces cerevisiae Based on Studies with Tri- n -Alkyltin Chlorides

A Synergistic Effect of Select Organotin Compounds and Ionic Surfactants on Liposome Membranes

Bioaccumulation of TBT by Aquatic Organisms

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