title: Structure-toxicity relationship of monoketones: in vitro effects on beta-adrenergic receptor binding and Na(+)-K(+)-ATPase activity in mouse synaptosomes.
abstract: The structure-toxicity relationship of monoketones, a class of organic solvents widely used in industry, was investigated with respect to their in vitro effects on synaptosomal membrane proteins. The toxic parameters used were Na(+)-K(+)-adenosine triphosphatase (Na(+)-K(+)-ATPase), a well-known marker enzyme often used as a membrane toxicity model, and 3H-dihydroalprenolol (3H-DHA)-labeled beta-adrenergic receptor binding that has been shown to be vulnerable to solvent-induced changes in membrane fluidity. In vitro treatments with 12 kinds of monoketones (carbon chain length from 3-10) dose-dependently inhibited both 3H-DHA binding to mouse synaptosomes and Na(+)-K(+)-ATPase activity. The potency of inhibition (IC50) for both the two parameters was linearly related to n-octanol/water partition coefficient and synaptosome/buffer partition coefficient of the test compounds. Additions of monoketones did not significantly alter the number of 3H-DHA binding sites but markedly decreased their affinity. In each monoketone, the IC50 values for 3H-DHA binding and Na(+)-K(+)-ATPase activity were generally within the same range. The anisotropy of fluorescence probe 1,6-diphenyl-1,3,5-hexatriene-labeled synaptosomal membranes was dose-dependently decreased by the monoketones, implying increased membrane fluidity. These results indicate that increasing lipophilicity of monoketones results in increased solvent penetration of synaptic membrane preparations, leading to conformational changes in membrane structure and increased ability to inhibit both neuroreceptor binding and enzyme activity. The present data confirm the importance of the lipid micro-environment of membranes in maintaining the normal functions of membrane-bound proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Hygiene, School of Medicine, Kanazawa University, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: H
authors.initials: H
authors.lastname: Tanii
authors.forename: T
authors.initials: T
authors.lastname: Ohyashiki
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D004082:Dihydroalprenolol; D066298:In Vitro Techniques; D007659:Ketones / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology*
chemical_list: D007659:Ketones; D011941:Receptors, Adrenergic; D004082:Dihydroalprenolol; D000254:Sodium-Potassium-Exchanging ATPase