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the statins , by inhibiting hmg - coa reductase activity , reduce cholesterol and isoprenoid synthesis .
they have proven to be beneficial in preventing stroke   and may increase bone formation   and lower the risk of dementia .
essential fatty acids have several properties similar to the statins   and das   has suggested that " essential fatty acids and their metabolites may serve as second messengers of the actions of statins . "
mevastatin or lovastatin , at 25 m , induce pgi2 production and cyclooxygenase ( cox)-2 in human aorta smooth muscle cells .
mevalonate and geranylgeranyl - pyrophosphate block these stimulations implicating the cholesterol biosynthetic pathway in this up - regulation .
however , fluvastatin down - regulates rather than up - regulates cox-2 expression in human umbilical vein endothelial cells   and lovastatin reduces pgi2 production in bovine endothelial cells , human skin fibroblasts and arterial smooth muscle cells .
i observed that in rat liver cells , the statins stimulate the release of an essential fatty acid , arachidonic acid ( aa ) and stimulate production of its metabolite , pgi2 .
these stimulations are independent of hmg - coa reductase activity as measured by the lack of any suppression by mevalonate .
the release of aa from rat liver cells after 6 h incubation with mevastatin , lovastatin and simvastatin is shown in fig .
an extract of the pharmaceutical product lipitoralso significantly stimulates aa release ( data not shown ) .
the release of aa as a function of time in the presence of 50 m lovastatin or simvastatin is shown in fig .
2 . stimulation by lovastatin and simvastatin is observed after as little as 15 min incubation with cells ( the time of release with mevastatin was not studied ) .
preincubation of the cells for 2 h with 1 m actinomycin did not alter the quantity of aa release stimulated by 6 h incubation with simvastatin [ 17.0  0.30 % ( 5 ) was released in the absence of actinomycin compared to 17.6  0.60 % ( 5 ) released in its presence ] .
i have shown previously that under these conditions , induced pg production is inhibited . nor does mevalonate , the direct product of hmg - coa reductase , affect the stimulated release by 50 m simvastatin ( fig .
cells were incubated with these statins at the concentrations shown for 6 h. the analyses were performed on triplicate culture dishes .
time course of release of aa after incubation with 50 m lovastatin (  ) , 50 m simvastatin (  ) and the mem / bsa controls (  ) .
effect of 188 m mevalonate on aa release from rat liver cells incubated 6 h in the presence of 50 m simvastatin .
pgi2 production is enhanced in cells incubated with lactacystin in the presence of tpa ( fig .
even at 70 min the quantity of pgi2 produced by lactacystin plus tpa increased in the presence of 30 m simvastatin ( fig .
the effect of 96 m mevalonate on simvastatin 's amplification of induced pgi2 in the presence of lactacystin plus tpa is shown in fig .
mevalonate amplifies even further the effect of simvastatin on lactacystin plus tpa induced pgi2 production , suggesting a role for a downstream isoprenoid in the induction pathway ( fig .
effect of 27 m simvastatin , 100 m mevastatin and 50 m lovastatin on lactacystin plus tpa induced 6-keto - pgf1 production after 6 h incubation . at the levels
tested , simvastatin , mevastatin and lovastatin alone do significantly stimulate basal pgi2 production , but by < 1 ng / ml . the analyses were performed on triplicate dishes . *
time course of 6-keto - pgf1 production during incubation with mem / bsa (  ) , 30 m simvastatin (  ) , lactacystin plus tpa (  ) and lactacystin plus tpa plus 30 m simvastatin ( * ) .
effect of 96 m mevalonate on 6-keto - pgf1 produced by stimulation with 30 m simvastatin in the presence of lactacystin plus tpa after a 6 h incubation .
* statistically significant vs lactacystin plus tpa ( p < 0.05 ) * * statistically significant vs lactacystin plus tpa and simvastatin ( p < 0.05 ) .
mevastatin , lovastatin , simvastatin and atorvastatin stimulate the release of aa from rat liver cells .
mevalonate , the product of hmg - coa reductase , does not suppress simvastatin 's stimulated aa release .
therefore , it appears that neither transcription nor cholesterol biosynthesis is required for this stimulated aa release .
hmg - coa reductase activity also is not required for up - regulation of induced pgi2 production by simvastatin .
aa also activates leukocyte nadph oxidase , activates ppar receptors , affects hchannel , kchannel   and ca channel activities .
it elevates heat shock gene expression , induces apoptosis   and inhibits ca induced ca release . in human embryonic kidney cells it down - regulates sterol regulatory element - binding proteins ( srebps ) , especially the srebp-1a isoform .
the release of aa after incubation with sulindac and the stimulation of apoptosis via conversion of sphingomyelin to ceramide   is a mechanism proposed to mediate cancer chemoprevention by nonsteroidal anti - inflammatory drugs .
i have postulated that , in addition to nonsteroidal anti - inflammatory drugs , the continuous use of other commonly prescribed drugs that release aa is potentially cancer preventative .
the major product of pgh2 metabolism by these rat liver cells is pgi2 , although 10% or less of the metabolites are pge2 and pgf2 . in this study ,
although pgi2 synthase is an induced enzyme , the increased pgi2 production probably reflects cox activity . up - regulation of pgi2 production is in agreement with the findings of degreave et al   who showed that mevastatin and lovastatin up - regulate cox activity in human aortic smooth muscle cells .
however , while up - regulation in the muscle cell system involves cholesterol biosynthesis , the up - regulation observed in rat liver cells does not .
statins also have been shown to down - regulate cox activity in human umbilical vein endothelial cells .
in addition to differences inherent in the type of cells being studied by the various investigators , the apparently contradictory findings may also be due to examination of the cells at different stages of growth .
the published studies [ 11 - 13 ] use cells at confluent densities and also may have been in the g0 stage of growth .
the rat liver cells studied in this report were at low density ( dividing cells ) .
since statins activate at m concentrations , it is likely that the release of aa and effects on pgi2 production are reflections of interaction with cell membranes .
however , in view of the many biological activities of aa , its release could generate the essential fatty acid that is postulated to be a mediator of statin action .
the c-9 rat liver cell line was purchased from the american type culture collection ( manassa , va , usa ) .
the cells were maintained in eagle 's minimum essential medium ( mem ) supplemented with 10% fetal bovine serum .
the [ h ] aa ( 91.8 ci / mmol ) was from nen life science products , inc .
mevastatin , lovastatin , dl - mevalonic acid lactone were from sigma chemical co. ( st .
gregory r. mundy , institute for drug development , san antonio , tx , for the generous supply of simvastatin . for the experiments with atorvastatin , ch3ch2oh and ch3oh
on the day prior to experiments , the rat liver cells were treated with 0.25% trypsin - edta and , after addition of minimal essential media ( mem ) containing 10% fetal calf serum , the floating cells were seeded onto 35 mm culture dishes .
after decantation of mem containing the fetal bovine serum , 1.0 ml fresh mem containing 10% fetal bovine serum and [ h ] aa ( 0.2 ci / ml ) was added and the cells incubated for another 24 h. the cells were washed 4 times with mem and incubated for various periods of time with 1.0 ml of different concentrations of each compound in mem containing 1.0 mg bsa / ml .
the culture fluids were then decanted , centrifuged at 2000  g for 10 min , and 200 l of the supernate counted for radioactivity .
radioactivity recovered in the washes before the 6 h incubation was compared to input radioactivity to calculate the % radioactivity incorporated into the cells .
for pgi2 production , 1.0 ml of mem supplemented with 10% fetal bovine serum , void of [ h ] aa , was added after the first 24 h incubation .
the cells were incubated for another 24 h , washed three times with mem , then incubated with lactacystin plus tpa and the compounds in mem containing bsa for various periods of time .
the culture fluids were decanted and analyzed for 6-keto - pgf1 , the stable hydrolytic product of pgi2 , by radioimmunoassay .
the [ h ] aa release is presented as a percentage of the radioactivity incorporated by the cells .
armen tashjian jr . , department of cancer cell biology , harvard school of public health , for his continuing interest in these studies .
statins inhibit 3-hydroxy-3-methylglutaryl ( hmg - coa ) reductase , the rate limiting step in cholesterol synthesis . 
 they are , therefore , used clinically to lower cholesterol and prevent atherosclerosis . 
 statins have beneficial effects on multiple organ systems . 
 some of these effects are found in the absence of significant changes in cholesterol levels . polyunsaturated 
 fatty acids also inhibit hmg - coa reductase and have many of the same beneficial effects of statins . 
 four statins ( mevastatin , lovastatin , simvastatin and atorvastatin ) have been tested in rat liver cells for their effect on arachidonic acid ( aa ) release and prostaglandin i2 production induced in the presence of lactacystin and 12-o - tetradecanoylphorbol-13-acetate . 
 each statin stimulated release of aa and induced prostaglandin i2 production . 
 mevalonate , the product of hmg - coa reductase , did not reduce the stimulation observed in the presence of simvastatin indicating that hmg - coa reductase activity is not involved . in view of the multiple biologic properties of aa , 
 the aa released as a result of the action of the statins may play a role in some of the pharmacological effects attributed to these drugs .