Inhibition of hepatic cholesterol biosynthesis by a 3-hydroxy-3-methylglutaryl coenzyme a synthase inhibitor, 1233A, in mice

Hajime Nagashima, Hidetoshi Kumagai, Hiroshi Tomoda, Satoshi Omura

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

We have studied the in vivo inhibition of hepatic sterol biosynthesis by 1233A, a specific inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase. Administration of the compound orally to mice resulted in a dose-dependent inhibition of [14C]acetate incorporation into sterols in liver, but did not exert any significant effect on [14C]mevalonate incorporation. The results indicate that the in vivo inhibition of sterol synthesis occurs only at pre-mevalonate enzymatic steps in the sterol biosynthetic pathway, thus being compatible with the presumed site of inhibition, HMG-CoA synthase. Moreover, owing to irreversible inactivation of the enzyme by 1233A, it was possible to detect in vivo effect on the enzyme by assays of its activity in cell-free extracts from liver; the drug-treatment also resulted in a similarly dose-dependent inhibition of HMG-CoA synthase activity. In contrast, acetoacetyl-CoA thiolase and HMG-CoA reductase, the enzymes also responsible for mevalonate synthesis in the pathway, did not show any significant change in activity. These results clearly demonstrate that the inhibition of hepatic sterol synthesis cause by 1233A is indeed due to selective inhibition of HMG-CoA synthase in the tissues.

Original languageEnglish (US)
Pages (from-to)1595-1600
Number of pages6
JournalLife Sciences
Volume52
Issue number19
DOIs
StatePublished - 1993

Fingerprint

antibiotic 1233A
Hydroxymethylglutaryl-CoA Synthase
Biosynthesis
Coenzymes
Sterols
Mevalonic Acid
Cholesterol
Liver
Acetyl-CoA C-Acetyltransferase
Enzymes
Drug therapy
Liver Extracts
Biosynthetic Pathways
Enzyme Assays
Enzyme Inhibitors
Cell Extracts
Assays
Oxidoreductases
Acetates
Tissue

ASJC Scopus subject areas

  • Pharmacology

Cite this

Inhibition of hepatic cholesterol biosynthesis by a 3-hydroxy-3-methylglutaryl coenzyme a synthase inhibitor, 1233A, in mice. / Nagashima, Hajime; Kumagai, Hidetoshi; Tomoda, Hiroshi; Omura, Satoshi.

In: Life Sciences, Vol. 52, No. 19, 1993, p. 1595-1600.

Research output: Contribution to journalArticle

Nagashima, Hajime ; Kumagai, Hidetoshi ; Tomoda, Hiroshi ; Omura, Satoshi. / Inhibition of hepatic cholesterol biosynthesis by a 3-hydroxy-3-methylglutaryl coenzyme a synthase inhibitor, 1233A, in mice. In: Life Sciences. 1993 ; Vol. 52, No. 19. pp. 1595-1600.
@article{9e3287491d984169b3d18313098ea23c,
title = "Inhibition of hepatic cholesterol biosynthesis by a 3-hydroxy-3-methylglutaryl coenzyme a synthase inhibitor, 1233A, in mice",
abstract = "We have studied the in vivo inhibition of hepatic sterol biosynthesis by 1233A, a specific inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase. Administration of the compound orally to mice resulted in a dose-dependent inhibition of [14C]acetate incorporation into sterols in liver, but did not exert any significant effect on [14C]mevalonate incorporation. The results indicate that the in vivo inhibition of sterol synthesis occurs only at pre-mevalonate enzymatic steps in the sterol biosynthetic pathway, thus being compatible with the presumed site of inhibition, HMG-CoA synthase. Moreover, owing to irreversible inactivation of the enzyme by 1233A, it was possible to detect in vivo effect on the enzyme by assays of its activity in cell-free extracts from liver; the drug-treatment also resulted in a similarly dose-dependent inhibition of HMG-CoA synthase activity. In contrast, acetoacetyl-CoA thiolase and HMG-CoA reductase, the enzymes also responsible for mevalonate synthesis in the pathway, did not show any significant change in activity. These results clearly demonstrate that the inhibition of hepatic sterol synthesis cause by 1233A is indeed due to selective inhibition of HMG-CoA synthase in the tissues.",
author = "Hajime Nagashima and Hidetoshi Kumagai and Hiroshi Tomoda and Satoshi Omura",
year = "1993",
doi = "10.1016/0024-3205(93)90060-G",
language = "English (US)",
volume = "52",
pages = "1595--1600",
journal = "Life Sciences",
issn = "0024-3205",
publisher = "Elsevier Inc.",
number = "19",

}

TY - JOUR

T1 - Inhibition of hepatic cholesterol biosynthesis by a 3-hydroxy-3-methylglutaryl coenzyme a synthase inhibitor, 1233A, in mice

AU - Nagashima, Hajime

AU - Kumagai, Hidetoshi

AU - Tomoda, Hiroshi

AU - Omura, Satoshi

PY - 1993

Y1 - 1993

N2 - We have studied the in vivo inhibition of hepatic sterol biosynthesis by 1233A, a specific inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase. Administration of the compound orally to mice resulted in a dose-dependent inhibition of [14C]acetate incorporation into sterols in liver, but did not exert any significant effect on [14C]mevalonate incorporation. The results indicate that the in vivo inhibition of sterol synthesis occurs only at pre-mevalonate enzymatic steps in the sterol biosynthetic pathway, thus being compatible with the presumed site of inhibition, HMG-CoA synthase. Moreover, owing to irreversible inactivation of the enzyme by 1233A, it was possible to detect in vivo effect on the enzyme by assays of its activity in cell-free extracts from liver; the drug-treatment also resulted in a similarly dose-dependent inhibition of HMG-CoA synthase activity. In contrast, acetoacetyl-CoA thiolase and HMG-CoA reductase, the enzymes also responsible for mevalonate synthesis in the pathway, did not show any significant change in activity. These results clearly demonstrate that the inhibition of hepatic sterol synthesis cause by 1233A is indeed due to selective inhibition of HMG-CoA synthase in the tissues.

AB - We have studied the in vivo inhibition of hepatic sterol biosynthesis by 1233A, a specific inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase. Administration of the compound orally to mice resulted in a dose-dependent inhibition of [14C]acetate incorporation into sterols in liver, but did not exert any significant effect on [14C]mevalonate incorporation. The results indicate that the in vivo inhibition of sterol synthesis occurs only at pre-mevalonate enzymatic steps in the sterol biosynthetic pathway, thus being compatible with the presumed site of inhibition, HMG-CoA synthase. Moreover, owing to irreversible inactivation of the enzyme by 1233A, it was possible to detect in vivo effect on the enzyme by assays of its activity in cell-free extracts from liver; the drug-treatment also resulted in a similarly dose-dependent inhibition of HMG-CoA synthase activity. In contrast, acetoacetyl-CoA thiolase and HMG-CoA reductase, the enzymes also responsible for mevalonate synthesis in the pathway, did not show any significant change in activity. These results clearly demonstrate that the inhibition of hepatic sterol synthesis cause by 1233A is indeed due to selective inhibition of HMG-CoA synthase in the tissues.

UR - http://www.scopus.com/inward/record.url?scp=0027518774&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027518774&partnerID=8YFLogxK

U2 - 10.1016/0024-3205(93)90060-G

DO - 10.1016/0024-3205(93)90060-G

M3 - Article

C2 - 8097863

AN - SCOPUS:0027518774

VL - 52

SP - 1595

EP - 1600

JO - Life Sciences

JF - Life Sciences

SN - 0024-3205

IS - 19

ER -