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Atorvastatin and simvastatin have distinct effects on hydroxy methylglutaryl-CoA reductase activity and mRNA abundance in the guinea pig

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Lipids

Abstract

The effects of atorvastatin and simvastatin on hydroxy methylglutary (HMG)-CoA reductase activity and mRNA abundance were studied in guinea pigs randomized to three groups: untreated animals and those treated with 20 mg/kg of atorvastatin or simvastatin. Guinea pigs were fasted for 0, 6, 12, or 18 h in an attempt to remove the drug from their systems. Reductase activity and mRNA levels were analyzed after each time point. Reductase inhibitor treatment resulted in 50–60% lower cholesterol concentrations compared to untreated guinea pigs (P<0.0001), while plasma triacylglycerol (TAG) concentrations did not differ among groups. Plasma cholesterol and TAG were 50–70% lower after 18 h fasting in the three groups (P<0.001). In the nonfasting state, simvastatin and atorvastatin treatment did not affect HMG-CoA reductase activity compared with untreated animals. However, after 6 h of fasting, simvastatin-treated guinea pigs had higher HMG-CoA reductase activity than untreated animals (P<0.01), suggesting that the drug had been removed from the enzyme. In contrast, atorvastatin-treated guinea pigs maintained low enzyme activity even after 18 h of fasting. Further, HMG-CoA reductase mRNA abundance was increased by sevenfold after atorvastatin treatment and by twofold after simvastatin treatment (P<0.01). These results suggest that sinvastatin and atorvastatin have different half-lives, which may affect HMG-CoA reductase mRNA levels. The increase in reductase activity by simvastatin during fasting could be related to an effect of this statin in stabilizing the enzyme. In contrast, atorvastatin, possibly due to its longer half-life, prolonged inhibition of HMG-CoA reductase activity and resulted in a greater increase in mRNA synthesis.

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Abbreviations

DEPC:

diethylpyrocarbonate

HMG:

hydroxy methyl glutaryl

LDL:

low density lipoprotein

SDS:

sodium dodecyl sulfate

TAG:

thiacyl-glycerol

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Authors and Affiliations

  1. Department of Nutritional Sciences, University of Connecticul, 3624 Horsebare Rd., 06269, Storrs, Connecticut

    Karin Conde, Suheeta Roy, Hedley C. Freake & Maria Luz Fernandez

  2. Warner-Lambert Division, Parke-Davis Pharmaceutical, 3624 Horsebare Rd., 48105, Ann Arbor, Michigan

    Roger S. Newton

Authors
  1. Karin Conde
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  2. Suheeta Roy
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  3. Hedley C. Freake
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  4. Roger S. Newton
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  5. Maria Luz Fernandez
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Correspondence to Maria Luz Fernandez.

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Conde, K., Roy, S., Freake, H.C. et al. Atorvastatin and simvastatin have distinct effects on hydroxy methylglutaryl-CoA reductase activity and mRNA abundance in the guinea pig. Lipids 34, 1327–1332 (1999). https://doi.org/10.1007/s11745-999-0485-2

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  • DOI: https://doi.org/10.1007/s11745-999-0485-2

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