Effects of buthiobate, a fungicide, on cytochrome P-450 of rat liver microsomes.

Yoshida, Yuzo; Aoyama, Yuri

doi:10.1248/bpb1978.8.432

Cited by 8 publications

(2 citation statements)

References 15 publications

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“…Such substrate specificities can be explained by a limited number of amino acid substitutions in substrate recognition sites 1, 2, and 5 between mammalian and fungal CYP51, and it is likely that these locations are responsible for conferring selectivity for sterol metabolism (Yoshida et al, 1997). Before the sequences of fungal and human CYP51 were known, this enzyme was identified as an antifungal therapeutic target that could be inhibited by many imidazole, triazole (Vanden Bossche et al, 1987Hartman and Sanglard, 1997;Kelly et al, 1997), and nonazole compounds (Aoyama et al, 1983Yoshida and Aoyama, 1985;Gebhardt et al, 1994;Hartman and Sanglard, 1997). Many of these marketed compounds are specific toward a single fungal species, whereas others have widespread application (Hartman and Sanglard, 1997).…”

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confidence: 99%

Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

Ekins¹,

Mankowski²,

Hoover³

et al. 2006

Drug Metab Dispos

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ABSTRACT:CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential mono-oxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, whereas inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. This study has demonstrated the potential for ligand-based computational pharmacophore modeling of human CYP51 and enables a high-throughput screening system for drug discovery and data base mining.

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mentioning

confidence: 99%

Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

Ekins¹,

Mankowski²,

Hoover³

et al. 2006

Drug Metab Dispos

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“…The use of buthiobate (S-n-butyl S'-p-t-butylbenzyl N-3-pyridyldithiocarbonimidate) in mammalian cell-culture studies was not previously reported. It was found to block lanosterol 14a-demethylase in yeast cells (Kato & Kawase, 1976;Aoyama et al, 1983) and in rat liver microsomal preparations (Yoshida & Aoyama, 1985). Triparanol { 1 - [p-(,8-diethylaminoethoxy)phenyl]-1 -(p-tolyl)-2-(pchlorophenyl)ethanol} was used as an inhibitor of desmosterol A24-reductase (Avigan et al, 1960;Gibbons & Pullinger, 1977 (Chen, 1967) and loaded with palmitate (Fluka A. G.; 10 mol of palmitate/g of albumin; Spector & Hoak, 1969).…”

Section: Introductionmentioning

confidence: 99%

Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in human hepatoma cell line Hep G2. Effects of inhibitors of cholesterol synthesis on enzyme activity

Boogaard¹,

Griffioen²,

Cohen³

1987

Biochemical Journal

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Incubating Hep G2 cells for 18 h with triparanol, buthiobate and low concentrations (< 0.5 /uM) of U18666A, inhibitors of desmosterol A24-reductase, of lanosterol l4x-demethylase and of squalene-2,3-epoxide cyclase (EC 5.4.99.7) respectively, resulted in a decrease of the HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase activity. However, U18666A at concentrations higher than 3/tM increased the HMG-CoA reductase activity in a concentration-dependent manner. None of these inhibitors influenced directly the reductase activity in Hep G2 cell homogenates. Analysis by t.l.c. of 14C-labelled non-saponifiable lipids formed from either [14C]acetate or [14C]mevalonate during the cell incubations confirmed the sites of action of the drugs used. Beside the 14C-labelled substrates of the blocked enzymes and 14C-labelled cholesterol, another non-saponifiable lipid fraction was observed, which behaves as polar sterols on t.l.c. This was the case with triparanol and at those concentrations of U18666A that decreased the reductase activity, suggesting that polar sterols may play a role in suppressing the reductase activity.In the presence of 30/SM-Ut8666A (sterol formation blocked) the increase produced by simultaneously added compactin could be prevented by addition of mevalonate. This indicates the existence of a non-sterol mevalonate-derived effector in addition to a sterol-dependent regulation. LDL (low-density lipoprotein), which was shown to be able to decrease the compactin-induced increase in reductase activity, could not prevent the U18666A-induced increase. On the contrary, LDL enhanced the U18666A effect, showing that the LDL regulation is not merely the result of introducing cholesterol to the cells.

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The discovery and development of fungicides—does biochemistry have a role?

Kuhn

1989

Pestic. Sci.

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While the parts played by synthesis chemists, biologists and toxicologists in the discovery and development of fungicides are well established, the role of the biochemist is generally less well appreciated. Biochemistry does, however, have an important contribution to make, the principal activities being: mode of action studies; generation of data on the intrinsic activities of molecules; biorational design of novel inhibitors; fungicide resistance; and molecular biology and its applications. The background to each of these areas and relevance to fungicide discovery and development are described. Examples from studies on ergosterol biosynthesis inhibitors are used to illustrate the discussion.

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Effects of buthiobate, a fungicide, on cytochrome P-450 of rat liver microsomes.

Cited by 8 publications

References 15 publications

Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in human hepatoma cell line Hep G2. Effects of inhibitors of cholesterol synthesis on enzyme activity

The discovery and development of fungicides—does biochemistry have a role?

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