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Journal of Lipid Research, Vol 36, 1294-1304, Copyright © 1995 by Lipid Research, Inc.
R Ramharack, MA Spahr, GW Hicks, KA Kieft, DW Brammer, LL Minton and RS Newton
Eight male cynomolgus monkeys (Macaca fascicularis) on a normal chow diet
were orally administered gemfibrozil daily using a weekly rising dose
protocol for 3 weeks (50, 125, and 200 mg/kg per day). At these drug doses,
Lp[a] levels were reduced: 83.7% +/- 3.2 (SEM), (P < 0.024); 63.7% +/-
4.1 (P < 0.013); and 36.2% +/- 1.1 (P < 0.002), respectively, of
pretreatment values. Lp[a] reduction was directly related to blood
gemfibrozil concentration (range 36-428 microM, r = 0.969) and occurred
without concomitant changes in apolipoprotein B. Three weeks posttreatment
Lp[a] levels returned to pretreatment values. A specific ribonuclease
protection assay demonstrated that liver apolipoprotein[a] (apo[a]) mRNA
expression was decreased in all animals to an average of 19.1% +/- 3.0 (P
< 0.0026), of pretreatment values after the 200 mg/kg treatment,
whereas, albumin, apolipoprotein A-I, apolipoprotein E, and
glyceraldehyde-3-phosphate dehydrogenase mRNAs were unchanged. Lp[a] levels
were unaffected by gemfibrozil in HepG2 cells permanently transfected with
an apo[a] 10-kringle cDNA construct containing partial 5'- and
3'-untranslated sequences and under control of a constitutive CMV promoter.
However, both Lp[a] and apo[a] mRNA in primary cynomolgus monkey
hepatocytes were coordinately lowered in a dose-dependent fashion by
gemfibrozil. Thus, Lp[a] can be regulated by gemfibrozil at the level of
apo[a] mRNA expression.
ARTICLES
Gemfibrozil significantly lowers cynomolgus monkey plasma lipoprotein[a]-protein and liver apolipoprotein[a] mRNA levels
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
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