Effects of Pravastatin on Cholesterol Metabolism in Watanabe Heritable Hyperlipidemic Rabbits
Pravastatin, a competitive inhibitor of hydroxymethylglutaryl CoA reductase (HMG CoA reductase) is a potent hypocholesterolemic agent in humans as well as experimental animals, including the Watanabe heritable hyperlipidemic (WHHL) rabbit, lacking low density lipoprotein (LDL) receptor activity. We...
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| Veröffentlicht in: | Japanese Heart Journal 1992, Vol.33(4), pp.451-463 |
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| creator | AMOROSA, Louis F. ROZOVSKI, S. Jamie ANANTHAKRISHNAN, Radha COLY, Erasme ALHINAI, Ali MARTUCCI, Charles SCHNEIDER, Stephen H. SHIMAMURA, Tetsuo KHACHADURIAN, Avedis K. |
| description | Pravastatin, a competitive inhibitor of hydroxymethylglutaryl CoA reductase (HMG CoA reductase) is a potent hypocholesterolemic agent in humans as well as experimental animals, including the Watanabe heritable hyperlipidemic (WHHL) rabbit, lacking low density lipoprotein (LDL) receptor activity. We studied the effect of pravastatin on several aspects of cholesterol metabolism in WHHL rabbits. Cholesterol synthesis was measured by intraperitoneal injection of radioacetate and determination of its incorporation into the nonsaponifiable lipid fraction of liver, plasma, adrenal glands and gonads. A single dose of pravastatin (25mg/kg) caused statistically significant inhibition of hepatic cholesterol synthesis at 2, 6, 12, and 24 hours following oral administration. By 48 hours, the inhibitory effect of the drug was no longer demonstrable. The pattern of radioactivity in the plasma was similar to that in the liver. The drug had no statistically significant effect on cholesterol synthesis in adrenal glands and gonads, suggesting a selective effect on the liver. Cholesterol absorption was studied after simultaneous oral administration of [3H] cholesterol and [14C] β-sitosterol. Pravastatin, 50mg/kg for 10 days had no effect on fecal excretion of the radiolabelled steroids over 4 days. At 24 hours the plasma level of [14C] cholesterol was 1/3 that of control in pravastatin treated animals (p |
| doi_str_mv | 10.1536/ihj.33.451 |
| format | Article |
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Jamie ; ANANTHAKRISHNAN, Radha ; COLY, Erasme ; ALHINAI, Ali ; MARTUCCI, Charles ; SCHNEIDER, Stephen H. ; SHIMAMURA, Tetsuo ; KHACHADURIAN, Avedis K.</creator><creatorcontrib>AMOROSA, Louis F. ; ROZOVSKI, S. Jamie ; ANANTHAKRISHNAN, Radha ; COLY, Erasme ; ALHINAI, Ali ; MARTUCCI, Charles ; SCHNEIDER, Stephen H. ; SHIMAMURA, Tetsuo ; KHACHADURIAN, Avedis K.</creatorcontrib><description>Pravastatin, a competitive inhibitor of hydroxymethylglutaryl CoA reductase (HMG CoA reductase) is a potent hypocholesterolemic agent in humans as well as experimental animals, including the Watanabe heritable hyperlipidemic (WHHL) rabbit, lacking low density lipoprotein (LDL) receptor activity. We studied the effect of pravastatin on several aspects of cholesterol metabolism in WHHL rabbits. Cholesterol synthesis was measured by intraperitoneal injection of radioacetate and determination of its incorporation into the nonsaponifiable lipid fraction of liver, plasma, adrenal glands and gonads. A single dose of pravastatin (25mg/kg) caused statistically significant inhibition of hepatic cholesterol synthesis at 2, 6, 12, and 24 hours following oral administration. By 48 hours, the inhibitory effect of the drug was no longer demonstrable. The pattern of radioactivity in the plasma was similar to that in the liver. The drug had no statistically significant effect on cholesterol synthesis in adrenal glands and gonads, suggesting a selective effect on the liver. Cholesterol absorption was studied after simultaneous oral administration of [3H] cholesterol and [14C] β-sitosterol. Pravastatin, 50mg/kg for 10 days had no effect on fecal excretion of the radiolabelled steroids over 4 days. At 24 hours the plasma level of [14C] cholesterol was 1/3 that of control in pravastatin treated animals (p<0.05) but did not undergo an accelerated decline over 6 days. The activity of acyl CoA: cholesterol acyltransferase (ACAT) in intestinal mucosa and the concentration of hepatic cholesterol were similar in animals treated over one year with pravastatin 50mg/kg/day or with placebo. Our data do not allow us to make definitive conclusions about the effect of pravastatin on cholesterol absorption but are compatible with the hypothesis that the drug inhibits the hepatic synthesis as well as the assembly of cholesterol into lipoproteins.</description><identifier>ISSN: 0021-4868</identifier><identifier>EISSN: 1348-673X</identifier><identifier>DOI: 10.1536/ihj.33.451</identifier><identifier>PMID: 1453550</identifier><identifier>CODEN: JHEJAR</identifier><language>eng</language><publisher>Tokyo: International Heart Journal Association</publisher><subject>Absorption ; Acyl CoA: acyltransferase ; Acyl Coenzyme A - metabolism ; Animals ; Biological and medical sciences ; Cholesterol - biosynthesis ; Cholesterol - metabolism ; Cholesterol synthesis and absorption ; General and cellular metabolism. Vitamins ; Hyperlipidemias - genetics ; Hyperlipidemias - metabolism ; Intestinal Mucosa - enzymology ; Liver - enzymology ; Medical sciences ; Pharmacology. Drug treatments ; Pravastatin ; Pravastatin - pharmacology ; Rabbits ; Sterol O-Acyltransferase - metabolism ; Time Factors ; Watanabe heritable hyperlipidemic rabbits (WHHL)</subject><ispartof>Japanese Heart Journal, 1992, Vol.33(4), pp.451-463</ispartof><rights>by International Heart Journal Association</rights><rights>1993 INIST-CNRS</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c574t-d3677105b78b8e76a1371b3279c6364b3c2e93ad9eb600a677540dd0f6d4add63</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1881,4022,27922,27923,27924</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4412348$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1453550$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>AMOROSA, Louis F.</creatorcontrib><creatorcontrib>ROZOVSKI, S. Jamie</creatorcontrib><creatorcontrib>ANANTHAKRISHNAN, Radha</creatorcontrib><creatorcontrib>COLY, Erasme</creatorcontrib><creatorcontrib>ALHINAI, Ali</creatorcontrib><creatorcontrib>MARTUCCI, Charles</creatorcontrib><creatorcontrib>SCHNEIDER, Stephen H.</creatorcontrib><creatorcontrib>SHIMAMURA, Tetsuo</creatorcontrib><creatorcontrib>KHACHADURIAN, Avedis K.</creatorcontrib><title>Effects of Pravastatin on Cholesterol Metabolism in Watanabe Heritable Hyperlipidemic Rabbits</title><title>Japanese Heart Journal</title><addtitle>Jpn Heart J</addtitle><description>Pravastatin, a competitive inhibitor of hydroxymethylglutaryl CoA reductase (HMG CoA reductase) is a potent hypocholesterolemic agent in humans as well as experimental animals, including the Watanabe heritable hyperlipidemic (WHHL) rabbit, lacking low density lipoprotein (LDL) receptor activity. We studied the effect of pravastatin on several aspects of cholesterol metabolism in WHHL rabbits. Cholesterol synthesis was measured by intraperitoneal injection of radioacetate and determination of its incorporation into the nonsaponifiable lipid fraction of liver, plasma, adrenal glands and gonads. A single dose of pravastatin (25mg/kg) caused statistically significant inhibition of hepatic cholesterol synthesis at 2, 6, 12, and 24 hours following oral administration. By 48 hours, the inhibitory effect of the drug was no longer demonstrable. The pattern of radioactivity in the plasma was similar to that in the liver. The drug had no statistically significant effect on cholesterol synthesis in adrenal glands and gonads, suggesting a selective effect on the liver. Cholesterol absorption was studied after simultaneous oral administration of [3H] cholesterol and [14C] β-sitosterol. Pravastatin, 50mg/kg for 10 days had no effect on fecal excretion of the radiolabelled steroids over 4 days. At 24 hours the plasma level of [14C] cholesterol was 1/3 that of control in pravastatin treated animals (p<0.05) but did not undergo an accelerated decline over 6 days. The activity of acyl CoA: cholesterol acyltransferase (ACAT) in intestinal mucosa and the concentration of hepatic cholesterol were similar in animals treated over one year with pravastatin 50mg/kg/day or with placebo. Our data do not allow us to make definitive conclusions about the effect of pravastatin on cholesterol absorption but are compatible with the hypothesis that the drug inhibits the hepatic synthesis as well as the assembly of cholesterol into lipoproteins.</description><subject>Absorption</subject><subject>Acyl CoA: acyltransferase</subject><subject>Acyl Coenzyme A - metabolism</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cholesterol - biosynthesis</subject><subject>Cholesterol - metabolism</subject><subject>Cholesterol synthesis and absorption</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Hyperlipidemias - genetics</subject><subject>Hyperlipidemias - metabolism</subject><subject>Intestinal Mucosa - enzymology</subject><subject>Liver - enzymology</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Pravastatin</subject><subject>Pravastatin - pharmacology</subject><subject>Rabbits</subject><subject>Sterol O-Acyltransferase - metabolism</subject><subject>Time Factors</subject><subject>Watanabe heritable hyperlipidemic rabbits (WHHL)</subject><issn>0021-4868</issn><issn>1348-673X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkcFrFDEUh4NY6rZ68S7MQTwUZk3mZZKZoyzVCpUWUfQi4SXzxs2SmVmT2UL_e1NnWS9J4Pt4v8cvjL0WfC1qUO_9drcGWMtaPGMrAbIplYafz9mK80qUslHNC3aR0o5zoaoGztm5kDXUNV-xX9d9T25OxdQX9xEfMM04-7GYxmKznQKlmeIUii80o52CT0OR4Q-ccURLxQ1Fn0HIr8c9xeD3vqPBu-IrWuvn9JKd9RgSvTrel-z7x-tvm5vy9u7T582H29LVWs5lB0prwWurG9uQVihACwuVbp0CJS24ilrAriWrOMcs15J3He9VJ7HrFFyyd8vcfZz-HPLSZvDJUQg40nRIRgMoXkObxatFdHFKKVJv9tEPGB-N4OapS5O7NAAmd5nlN8epBztQ919dysv87ZFjchj6iKPz6aRJKar8F1nbLNoud_ubThzj7F2gp0TRKv4vdTly-Im6LUZDI_wF_4WUGQ</recordid><startdate>1992</startdate><enddate>1992</enddate><creator>AMOROSA, Louis F.</creator><creator>ROZOVSKI, S. Jamie</creator><creator>ANANTHAKRISHNAN, Radha</creator><creator>COLY, Erasme</creator><creator>ALHINAI, Ali</creator><creator>MARTUCCI, Charles</creator><creator>SCHNEIDER, Stephen H.</creator><creator>SHIMAMURA, Tetsuo</creator><creator>KHACHADURIAN, Avedis K.</creator><general>International Heart Journal Association</general><general>Japanese Heart Journal Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>1992</creationdate><title>Effects of Pravastatin on Cholesterol Metabolism in Watanabe Heritable Hyperlipidemic Rabbits</title><author>AMOROSA, Louis F. ; ROZOVSKI, S. Jamie ; ANANTHAKRISHNAN, Radha ; COLY, Erasme ; ALHINAI, Ali ; MARTUCCI, Charles ; SCHNEIDER, Stephen H. ; SHIMAMURA, Tetsuo ; KHACHADURIAN, Avedis K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c574t-d3677105b78b8e76a1371b3279c6364b3c2e93ad9eb600a677540dd0f6d4add63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Absorption</topic><topic>Acyl CoA: acyltransferase</topic><topic>Acyl Coenzyme A - metabolism</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cholesterol - biosynthesis</topic><topic>Cholesterol - metabolism</topic><topic>Cholesterol synthesis and absorption</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Hyperlipidemias - genetics</topic><topic>Hyperlipidemias - metabolism</topic><topic>Intestinal Mucosa - enzymology</topic><topic>Liver - enzymology</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Pravastatin</topic><topic>Pravastatin - pharmacology</topic><topic>Rabbits</topic><topic>Sterol O-Acyltransferase - metabolism</topic><topic>Time Factors</topic><topic>Watanabe heritable hyperlipidemic rabbits (WHHL)</topic><toplevel>online_resources</toplevel><creatorcontrib>AMOROSA, Louis F.</creatorcontrib><creatorcontrib>ROZOVSKI, S. Jamie</creatorcontrib><creatorcontrib>ANANTHAKRISHNAN, Radha</creatorcontrib><creatorcontrib>COLY, Erasme</creatorcontrib><creatorcontrib>ALHINAI, Ali</creatorcontrib><creatorcontrib>MARTUCCI, Charles</creatorcontrib><creatorcontrib>SCHNEIDER, Stephen H.</creatorcontrib><creatorcontrib>SHIMAMURA, Tetsuo</creatorcontrib><creatorcontrib>KHACHADURIAN, Avedis K.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Japanese Heart Journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>AMOROSA, Louis F.</au><au>ROZOVSKI, S. Jamie</au><au>ANANTHAKRISHNAN, Radha</au><au>COLY, Erasme</au><au>ALHINAI, Ali</au><au>MARTUCCI, Charles</au><au>SCHNEIDER, Stephen H.</au><au>SHIMAMURA, Tetsuo</au><au>KHACHADURIAN, Avedis K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of Pravastatin on Cholesterol Metabolism in Watanabe Heritable Hyperlipidemic Rabbits</atitle><jtitle>Japanese Heart Journal</jtitle><addtitle>Jpn Heart J</addtitle><date>1992</date><risdate>1992</risdate><volume>33</volume><issue>4</issue><spage>451</spage><epage>463</epage><pages>451-463</pages><issn>0021-4868</issn><eissn>1348-673X</eissn><coden>JHEJAR</coden><abstract>Pravastatin, a competitive inhibitor of hydroxymethylglutaryl CoA reductase (HMG CoA reductase) is a potent hypocholesterolemic agent in humans as well as experimental animals, including the Watanabe heritable hyperlipidemic (WHHL) rabbit, lacking low density lipoprotein (LDL) receptor activity. We studied the effect of pravastatin on several aspects of cholesterol metabolism in WHHL rabbits. Cholesterol synthesis was measured by intraperitoneal injection of radioacetate and determination of its incorporation into the nonsaponifiable lipid fraction of liver, plasma, adrenal glands and gonads. A single dose of pravastatin (25mg/kg) caused statistically significant inhibition of hepatic cholesterol synthesis at 2, 6, 12, and 24 hours following oral administration. By 48 hours, the inhibitory effect of the drug was no longer demonstrable. The pattern of radioactivity in the plasma was similar to that in the liver. The drug had no statistically significant effect on cholesterol synthesis in adrenal glands and gonads, suggesting a selective effect on the liver. Cholesterol absorption was studied after simultaneous oral administration of [3H] cholesterol and [14C] β-sitosterol. Pravastatin, 50mg/kg for 10 days had no effect on fecal excretion of the radiolabelled steroids over 4 days. At 24 hours the plasma level of [14C] cholesterol was 1/3 that of control in pravastatin treated animals (p<0.05) but did not undergo an accelerated decline over 6 days. The activity of acyl CoA: cholesterol acyltransferase (ACAT) in intestinal mucosa and the concentration of hepatic cholesterol were similar in animals treated over one year with pravastatin 50mg/kg/day or with placebo. Our data do not allow us to make definitive conclusions about the effect of pravastatin on cholesterol absorption but are compatible with the hypothesis that the drug inhibits the hepatic synthesis as well as the assembly of cholesterol into lipoproteins.</abstract><cop>Tokyo</cop><pub>International Heart Journal Association</pub><pmid>1453550</pmid><doi>10.1536/ihj.33.451</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Japanese Heart Journal, 1992, Vol.33(4), pp.451-463 |
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| subjects | Absorption Acyl CoA: acyltransferase Acyl Coenzyme A - metabolism Animals Biological and medical sciences Cholesterol - biosynthesis Cholesterol - metabolism Cholesterol synthesis and absorption General and cellular metabolism. Vitamins Hyperlipidemias - genetics Hyperlipidemias - metabolism Intestinal Mucosa - enzymology Liver - enzymology Medical sciences Pharmacology. Drug treatments Pravastatin Pravastatin - pharmacology Rabbits Sterol O-Acyltransferase - metabolism Time Factors Watanabe heritable hyperlipidemic rabbits (WHHL) |
| title | Effects of Pravastatin on Cholesterol Metabolism in Watanabe Heritable Hyperlipidemic Rabbits |
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