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PubMed2001

Retrobiosynthetic nuclear magnetic resonance analysis of amino acid biosynthesis and intermediary metabolism. Metabolic flux in developing maize kernels.

Information on metabolic networks could provide the basis for the design of targets for metabolic engineering. To study metabolic flux in cereals, developing maize (Zea mays) kernels were grown in sterile culture on medium containing [U-(13)C(6)]glucose or [1,2-(13)C(2)]acetate. After growth, amino acids, lipids, and sitosterol were isolated from kernels as well as from the cobs, and their (13)C isotopomer compositions were determined by quantitative nuclear magnetic resonance spectroscopy. The highly specific labeling patterns were used to analyze the metabolic pathways leading to amino acids and the triterpene on a quantitative basis. The data show that serine is generated from phosphoglycerate, as well as from glycine. Lysine is formed entirely via the diaminopimelate pathway and sitosterol is synthesized entirely via the mevalonate route. The labeling data of amino acids and sitosterol were used to reconstruct the labeling patterns of key metabolic intermediates (e.g. acetyl-coenzyme A, pyruvate, phosphoenolpyruvate, erythrose 4-phosphate, and Rib 5-phosphate) that revealed quantitative information about carbon flux in the intermediary metabolism of developing maize kernels. Exogenous acetate served as an efficient precursor of sitosterol, as well as of amino acids of the aspartate and glutamate family; in comparison, metabolites formed in the plastidic compartments showed low acetate incorporation.

Amino Acids↗
PubMed1972

An interstrain difference in cholesterol synthesis in vitro in mice, dependent upon a difference in endogenous NADPH-generating capacity.

Earlier experiments have shown that significantly more endogenously generated NADPH is available for reduction of corticosterone in liver homogenates from C57BL/10 male mice than in those from the DBA/2 strain. To test the effect of this interstrain difference upon a representative NADPH-requiring biosynthetic pathway in vitro, the biosynthesis of cholesterol from mevalonic acid was studied in homogenates of livers from the two strains of mice, with and without addition of an NADPH-generating system. The incorporation of mevalonic acid into cholesterol in homogenates from the C57BL/10 strain is little affected by omission of the NADPH-generating system, but in the DBA/2 strain, addition of an NADPH-generating system is necessary to elevate the level of cholesterol synthesis to that of the C57BL/10 strain. Without this addition, the DBA/2 homogenate mainly produces lanosterol and other precursors of cholesterol which require NADPH for their further metabolism.

Animals↗
PubMed2003

Antioxidative potential of fluvastatin via the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity.

We previously reported that fluvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, a strong lipid lowering drug, exerted an anti-atherosclerotic effect at doses insufficient to lower serum lipids in cholesterol fed rabbits. The evidence demonstrated that the superoxide anions from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase plays a critical role in several steps in the development of atherosclerosis. This study was designed to determine the effects of HMG-CoA reductase inhibitors on the production of the superoxide anions of NADPH oxidase in isolated rat peritoneal neutrophils. Fluvastatin (1-10 microM) decreased phorbol 12-myristate 13-acetate (PMA, 10 nM)-dependent reactive oxygen species (ROS) generation in a concentration-dependent manner. It also (10 microM) decreased PMA-dependent O(2) consumption of the rat neutrophils. These effects were reversed by the addition of mevalonate, a metabolite in the HMG-CoA reductase pathway. Treatment with pravastatin did not show any significant changes. Fluvastatin (10 microM) decreased ROS, such as hydroxyl radicals and superoxide anions generated by the Fenton reaction, and by the xanthine-xanthine oxidase system. Rats were treated with either fluvastatin (5 mg/kg per day, p.o.) or pravastatin (5 mg/kg per day, p.o.) for 1 week. Treatment with fluvastatin decreased the PMA-dependent ROS generation. The fluvastatin induced effect on the PMA-dependent ROS generation was reversed by the combined administration with 40 mg/kg mevalonate per day. The antioxidative effect of fluvastatin was thought to have caused not only the scavenging action of the radicals but also to have inhibited ROS generation by inhibiting the NADPH oxidase activity. This antioxidative potential of fluvastatin via the inhibition of NADPH oxidase activity may be profitable in preventing atherosclerosis.

Administration, Oral↗
PubMed2003

Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation.

Mevalonate kinase (MK) is an essential enzyme in the isoprenoid biosynthesis pathway which produces numerous biomolecules (isoprenoids) involved in a variety of cellular processes. The indispensability of MK and isoprenoid biosynthesis for human health is demonstrated by the identification of its deficiency as the biochemical and molecular cause of the inherited autoinflammatory disorders mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. Since the discovery of the genetic defect, considerable progress has been made in understanding the molecular, biochemical and immunological basis of MK deficiency. Important questions such as which specific protein(s) and/or signaling pathway(s) are affected, however, remain unanswered. Resolving the complete pathophysiology of this disorder is a major challenge, but eventually will give insight into the in vivo role of MK and isoprenoid biosynthesis in inflammation and fever. This may open novel options for antiinflammatory therapies in general. Here, we give a general introduction on isoprenoid biosynthesis, the regulation thereof and deficiencies therein. We review the molecular, biochemical and immunological aspects of MK deficiency and discuss the relations between isoprenoid biosynthesis and inflammation. Finally, we compare MK deficiency with other autoinflammatory syndromes.

Cholesterol↗
PubMed1992

Inhibition of pancreatic adenocarcinoma cell growth by lovastatin.

RAS protein (p21 ras) requires farnesyl (an intermediate of cholesterol synthesis) for activation. Activating mutations of K-ras gene have been detected in most human pancreatic adenocarcinomas. In the present study, the effect of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A, the rate-limiting enzyme of cholesterol synthesis, on the growth of five pancreatic cancer cell lines (human-CAV, MIA Paca2, CAPAN2 and PANC1, and hamster-H2T) in vitro and of two cell lines (CAV and H2T) in vivo was examined. Inhibition of cell growth was observed with lovastatin doses at or above 2.5 micrograms/mL for H2T, CAV, MIA Paca2, and CAPAN2 or 10 micrograms/mL in PANC1. The H2T cell line was studied further to determine the reversibility of growth inhibition. Mevalonic acid (1 mmol/L) reversed lovastatin-induced inhibition of cell growth if it was added with lovastatin (2.5 micrograms/mL). Similarly, removal of lovastatin from the medium within 24 hours after treatment allowed recovery of cell growth. The effect of lovastatin on cell growth was irreversible after 48 hours of exposure. The survival fraction of H2T cells was markedly decreased by 1- or 24-hour exposure to 75 micrograms/mL but not to doses ranging from 0.5 to 60 micrograms/mL of lovastatin. Growth of pancreatic carcinoma xenografts (CAV and H2T) in nude mice was inhibited by a subcutaneous infusion of lovastatin (50 micrograms/h). These results indicate that mevalonic acid or a metabolite in the cholesterol synthesis pathway is necessary for growth of pancreatic cancer cells and suggest that lovastatin should be further examined as a potential therapeutic agent for pancreatic cancer.

Animals↗
PubMed1996

Inhibitory effect of fluvastatin at doses insufficient to lower serum lipids on the catheter-induced thickening of intima in rabbit femoral artery.

The anti-atherosclerotic effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors at doses insufficient to lower serum cholesterol was investigated in rabbit femoral artery denuded by balloon catheter. Fluvastatin and pravastatin were given orally at doses of 4 and 8 mg/kg per day, respectively, for 2 weeks after the catheterization. There was little change in serum cholesterol, triglyceride and phospholipid by chronic treatment with the drugs. The cross-sectional area of the intima, expressed as relative values to media (I/M ratio), was increased by the catheterization, showing intimal thickening in the denuded arteries. The I/M ratio was reduced by fluvastatin but not pravastatin: 0.327 +/- 0.060 for control, 0.116 +/- 0.035 for 4 mg/kg fluvastatin, 0.088 +/- 0.027 for 8 mg/kg fluvastatin and 0.22 +/- 0.069 for 8 mg/kg pravastatin. Fluvastatin (8 mg/kg)-induced effect on the I/M ratio, was prevented by the combined administration with 40 mg/kg per day mevalonate, a metabolite in the HMG-CoA reductase pathway. These results suggest that fluvastatin inhibits intimal thickening after catheterization-induced injury through percutaneous transluminal coronary angioplasty (PTCA) and that the inhibition is presumably attributed to reduced migration and proliferation of smooth muscle cells but not secondarily to a lowering of serum lipid.

Animals↗
PubMed1989

Mevalonate-metabolizing enzymes in Arachis hypogaea.

The activities of the mevalonate metabolizing enzymes-HMG-CoA reductase, mevalonate kinase, mevalonate phosphokinase and mevalonate pyrophosphate decarboxylase -were assayed with the respective substrates in green seedlings of Arachis hypogaea. MVAPP decarboxylase is the rate-limiting step among these enzymes and is inhibited by phenolic acids. Its activity in the seedlings was found to decrease in the absence of light and on treatment with abscisic acid. These results suggest that regulation of isoprene pathway in groundnut seedlings may occur at the level of mevalonate decarboxylation.

Abscisic Acid↗
PubMed2000

Nonequivalent labeling of the phytyl side chain of chlorophyll a in callus of the hornwort Anthoceros punctatus.

Callus cultures of the hornwort Anthoceros punctatus were induced from the apical portions of the gametophytes. Calli can accumulate rosmarinic acid, which is suggested as an intermediate for anthocerotonic acid, a rare phenylpropanoid dimer with a cyclobutane ring, indicating that calli possess the ability to produce secondary metabolites found primarily in intact plants. Biosynthesis of chloroplastidic terpenoids of liverworts showed preferential labeling of the farnesyl diphosphate (FPP)-derived portion in the phytyl side chain of chlorophyll a (1) when calli of A. punctatus are incubated with (2)H- and (13)C-labeled mevalonate. This finding suggests either that cytoplasmic FPP (or isopentenyl diphosphate, IPP) is taken into chloroplasts and condensed with endogenous IPP derived from a nonmevalonate pathway, or that FPP is synthesized within chloroplasts from extraplastidically formed IPP (or mevalonate) and then condensed with endogenous IPP in a different subplastidic fraction.

Antioxidants↗
PubMed2006

Molecular cloning of a HMG-CoA reductase gene from Eucommia ulmoides Oliver.

The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the conversion of HMG-CoA to mevalonate, which is the first committed step in the pathway for isoprenoid biosynthesis in plants. A full-length cDNA encoding HMGR (designated as EuHMGR, GenBank Accession No. AY796343) was isolated from Eucommia ulmoides by rapid amplification of cDNA ends (RACE). The full-length cDNA of EuHMGR comprises 2281 bp with a 1770-bp open reading frame (ORF) encoding a 590-amino-acid polypeptide with two trans-membrane domains revealed by bioinformatic analysis. Molecular modeling showed that EuHMGR is a new HMGR with a spatial structure similar to other plant HMGRs. The deduced protein has an isoelectric point (pI) of 6.89 and a calculated molecular weight of about 63 kDa. Sequence comparison analysis showed that EuHMGR had highest homology to HMGR from Hevea brasiliensis. As expected, phylogenetic tree analysis indicated that EuHMGR belongs to plant HMGR group. Tissue expression pattern analysis showed that EuHMGR is strongly expressed in the leaves and stems whereas it is only poorly expressed in the roots, which implies that EuHMGR may be a constitutively expressing gene. Functional complementation of EuHMGR in HMGR-deficient mutant yeast JRY2394 demonstrated that EuHMGR mediates the mevalonate biosynthesis in yeast.

Amino Acid Motifs↗
PubMed2006

Mevalonate kinase activity during different stages of plant regeneration from nodular callus cultures in white pine (Pinus strobus).

Mevalonate kinase (MK) catalyzes a step in the isoprenoid biosynthetic pathway, which leads to a huge number of compounds that play important roles in plant growth and development. Here, we report on changes in MK activity in white pine (Pinus strobus L.) during plant regeneration by adventitious shoot organogenesis from cotyledons of mature embryos, including nodular callus induction, shoot formation and rooting. Nodular calli were induced from Pinus strobus (PS) embryos by culture in nodular callus induction medium in a 0-, 8- or 16-h photoperiod. Mevalonate kinase activity peaked in nodular calli after three weeks of culture on nodular callus induction medium in a 16-h photoperiod, whereas frequency of nodular callus formation peaked after 4 weeks of culture on nodular callus induction medium in darkness. During adventitious shoot formation, MK activity peaked in shoots derived from dark-grown nodular calli after 3 weeks on bud formation medium, and frequency of shoot formation was highest in dark-grown nodular calli cultured on bud formation medium for 4 weeks. During rooting, MK activity peaked 2 weeks after transfer of adventitious shoots to rooting medium and rooting frequency was highest in adventitious shoots after 3 weeks on rooting medium. Although during nodular callus induction in darkness MK activity was inversely related to frequency of nodular callus formation, MK activity was highly correlated with frequency of shoot formation and with rooting frequency. The observed increase in MK activity preceding rooting suggests that MK could serve as a marker for rooting of white pine shoots in vitro.

Benzyl Compounds↗
PubMed1997

Plasma mevalonate concentrations in uremic patients.

Mevalonic acid (mevalonate or MVA), is an obligate precursor in the biosynthetic pathway of cholesterol. It is partially metabolized by the kidneys and its plasma concentrations are an index of endogenous cholesterol synthesis. The aim of the present study was to evaluate plasma MVA concentrations in uremic patients with different degrees of chronic renal failure (CRF; group A), and the effects of a single hemodialysis treatment on plasma MVA in a group of patients with end-stage renal disease (ESRD; group B). CRF patients exhibited a higher mean basal mevalonate concentration (13.3 +/- 6.5 ng/ml) than control subjects (4.68 +/- 1.32 ng/ml; P < 0.001). A statistically significant direct correlation was evident in CRF patients between mevalonate and creatinine plasma levels (r = 0.86; P < 0.001). A single hemodialysis treatment was associated with a significant reduction of plasma mevalonate concentrations four hours after the hemodialysis session (-57%; P < 0.001) and an increase up to the basal values 24 hours after the end of the treatment. In conclusion, our results demonstrated: (i) higher plasma MVA concentrations in patients with decreased renal function; (ii) a direct relationship between plasma MVA levels and the degree of kidney failure as expressed by creatinine plasma concentrations; and (iii) a clear cut reduction of elevated plasma MVA levels after a single hemodialysis treatment.

Adult↗
PubMed1992

Inhibition of cultured vascular smooth muscle cell migration by simvastatin (MK-733).

The effect of simvastatin (MK-733), a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the migration of cultured porcine smooth muscle cells (SMCs) was investigated in modified Boyden chambers. Platelet-derived growth factor (PDGF) stimulated the SMC migration dose dependently. MK-733 inhibited the migration response induced by PDGF with an IC50 value of 2 microM. Supplementation with mevalonate restored the migration response inhibited by MK-733 but the addition of low-density-lipoprotein (LDL) did not change the response. Another HMG-CoA reductase inhibitor, pravastatin (CS-514), also reduced the migration response. However its potency was far less than that of MK-733. MK-733 also inhibited the SMC migration stimulated by fibrinogen. These results suggest that non-sterol metabolite(s) of mevalonate, possibly prenylated proteins, are involved in a migration signaling pathway and that HMG-CoA reductase inhibitors are effective in the prevention of the formation of intimal hyperplasia in atherosclerosis.

Animals↗
PubMed2006

Lipophilic statins suppress cytotoxicity by freshly isolated natural killer cells through modulation of granule exocytosis.

NK cells, a component of the innate immune system, provide a first line of defense against viral infections and malignancies, interact with the adaptive immune system and have a role in rejection of allogeneic bone marrow transplants and solid allo- and xenotransplants. Immunoregulatory activity by the anti-hypercholesterolemia agents, 3-hydroxy-3-methyl-glutaryl Coenzyme A (HMG-CoA) reductase inhibitors, known as statins, has recently been reported. We analyzed the effects of three statins on human NK cell cytotoxicity. Two lipophilic statins (simvastatin and fluvastatin) suppressed the cytotoxic activity of fresh and IL-2-stimulated NK cells, while pravastatin, a hydrophilic statin, did not. Suppression was not associated with changes in intracellular perforin, granzyme A or granzyme B levels, or with changes in expression of leukocyte function-associated antigen-1, an integrin known to regulate NK activity and reported to be altered by statin treatment. Decreased cytotoxicity was associated with decreased CD107a surface expression, indicating that the exocytosis pathway was compromised by simvastatin and fluvastatin but not by pravastatin. Mevalonate, the immediate downstream product of HMG-CoA reductase, partially reversed the effect of lipophilic statins on cytotoxicity and CD107a expression. Lipophilic statins also suppressed the release of the granule component, granzyme B, by IL-2-activated NK cells following stimulation with K562. That lipophilic statins suppress NK cell activity through inhibition of the exocytosis pathway suggest an additional potential role for statins in inhibition of transplantation responses.

Cell Line↗
PubMed1992

Regulation of gibberellin formation by the fungus Gibberella fujikuroi.

Gibberellins are a classic example of the production of plant growth regulators by microorganisms. They are important biotechnological products and are increasingly used in agriculture and horticulture. The economic importance of these plant hormones has led to an extensive study of the regulation of gibberellin biosynthesis. There have been reports of light, growth rate, inoculum size and carbon and ammonium sources acting as regulators of gibberellic acid biosynthesis. Besides light stimulation, nitrogen repression is a well-known regulatory principle of secondary metabolite formation. In Gibberella fujikuroi ammonium interferes with the production of gibberellic acid whereas phosphate does not influence the biosynthesis. It was found that the negative effect of ammonium ions is due to both the inhibition of activity and the repression of de novo synthesis of specific gibberellin-producing enzymes. Besides nitrogen control, the biosynthesis of gibberellins is suppressed by glucose. This glucose effect can be overcome by the addition of mevalonic acid. Therefore, the key enzyme of the isoprenoid pathway, the HMG-CoA reductase, seems to be the target of C-catabolite repression. A detailed knowledge of the regulation of gibberellin biosynthesis is important for fermentation processes. The biological function of gibberellin formation for the producing fungus is discussed.

Carbon↗
PubMed1997

In vitro and in vivo antiproliferative effects of simvastatin, an HMG-CoA reductase inhibitor, on human glioma cells.

We analyzed the antiproliferative effect of simvastatin (SV), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on human glioma cell lines. Inhibition of cell growth with SV was observed in all cell lines tested. Different culture conditions altered this inhibition of growth: the lower the concentration of fetal bovine serum (FBS) in the medium, the higher the inhibitory effect of SV on glioma cells. On morphological examination, we found that most of the cells exposed to SV became rounded and the proportion of floating cells was increased in a time-dependent manner. Then we examined whether exogenously added mevalonic acid reversed the growth inhibitory effect of SV. Exogenous mevalonic acid suppressed the inhibitory effect of SV on glioma cells in a dose-dependent manner. SV also enhanced the expression of low-density lipoprotein (LDL) receptor on glioma cells. We also found that peroxidized LDL (p-LDL) was cytotoxic to glioma cells and that SV had additive effects on pLDL-induced cytotoxicity. In a mouse model, growth of glioma cells inoculated into nude mice was inhibited by intratumoral injection of both SV and peroxidized LDL. These results indicate that mevalonic acid or a metabolite in the cholesterol synthesis pathway is necessary for the growth of glioma cells and that simvastatin and/or peroxidized LDL should be examined further as potential therapeutic agents for gliomas.

Animals↗
PubMed2004

Comparison of mechanism and functional effects of magnesium and statin pharmaceuticals.

Since Mg(2+)-ATP is the controlling factor for the rate-limiting enzyme in the cholesterol biosynthesis sequence that is targeted by the statin pharmaceutical drugs, comparison of the effects of Mg(2+) on lipoproteins with those of the statin drugs is warranted. Formation of cholesterol in blood, as well as of cholesterol required in hormone synthesis, and membrane maintenance, is achieved in a series of enzymatic reactions that convert HMG-CoA to cholesterol. The rate-limiting reaction of this pathway is the enzymatic conversion of HMG CoA to mevalonate via HMG CoA. The statins and Mg inhibit that enzyme. Large trials have consistently shown that statins, taken by subjects with high LDL-cholesterol (LDL-C) values, lower its blood levels 35 to 65%. They also reduce the incidence of heart attacks, angina and other nonfatal cardiac events, as well as cardiac, stroke, and total mortality. These effects of statins derive less from their lowering of LDL-C than from their reduction of mevalonate formation which improves endothelial function, inhibits proliferation and migration of vascular smooth muscle cells and macrophages, promotes plaque stabilization and regression, and reduces inflammation, Mg has effects that parallel those of statins. For example, the enzyme that deactivates HMG-CoA Reductase requires Mg, making Mg a Reductase controller rather than inhibitor. Mg is also necessary for the activity of lecithin cholesterol acyl transferase (LCAT), which lowers LDL-C and triglyceride levels and raises HDL-C levels. Desaturase is another Mg-dependent enzyme involved in lipid metabolism which statins do not directly affect. Desaturase catalyzes the first step in conversion of essential fatty acids (omega-3 linoleic acid and omega-6 linolenic acid) into prostaglandins, important in cardiovascular and overall health. Mg at optimal cellular concentration is well accepted as a natural calcium channel blocker. More recent work shows that Mg also acts as a statin.

Anticholesteremic Agents↗
PubMed2002

Perturbation by geraniol of cell membrane permeability and signal transduction pathways in human colon cancer cells.

Geraniol, a natural component of plant essential oils, has antiproliferative effects on human colon cancer cells. To obtain more insight into its mechanism of action, we studied its effect on the resting membrane potential and on the expression of proteins involved in cell signaling pathways. Since geraniol is a well known inhibitor of mevalonate metabolism, the effect of mevalonate supplementation on geraniol-triggered growth inhibition was also determined. Geraniol (400 microM) induced membrane depolarization with a decrease of membrane resistance due to local perforation of the cell membrane. Incubation of Caco-2 cells with geraniol (400 microM) for 6 h caused a 60% reduction of protein kinase C (PKC) activity. After 16 h of incubation, geraniol decreased by 50% the amount of active forms of p44/p42 extracellular signal-regulated protein kinases (ERK). Mevalonate supplementation did not reverse inhibition of cell growth by geraniol. These results indicate that the antiproliferative effect of geraniol on Caco-2 cells was not related to a limitation of the mevalonate pool but was directly linked to the perturbation of cell membrane function leading to the reduction of PKC activity and to the decreased expression of p44/p42 ERK active forms.

Acyclic Monoterpenes↗
PubMed1990

Lovastatin and simvastatin--inhibitors of HMG CoA reductase and cholesterol biosynthesis.

The microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is a key rate-controlling step early in the cholesterol biosynthetic pathway that catalyzes the conversion of HMG CoA to mevalonic acid. Since this enzyme plays a significant role in regulating cholesterol synthesis, it is a rational target for pharmacologic intervention. The first potent, specific inhibitor of HMG CoA was mevastatin (compactin, ML-236B), which was discovered in 1976 by Endo et al. [J Antibiot 1976:29:1346-1348]. Subsequently, lovastatin, a novel, more active fungal metabolite was isolated from a strain of Aspergillus terreus. Lovastatin, the first of this class of agents to be approved for clinical use, was chemically modified to form simvastatin. Simvastatin is superior to lovastatin in intrinsic inhibitory potency. Both are inactive lactone prodrugs that must be converted to their respective dihydroxy open-acid forms to elicit inhibitory activity. Pharmacologic characterization of lovastatin and simvastatin has demonstrated that these potent inhibitors of HMG CoA reductase specifically inhibit cholesterol synthesis in animal cells, as well as in vivo after oral administration of the agents. Oral administration of either lovastatin or simvastatin to dogs in the presence or absence of the bile acid sequestrant cholestyramine results in a marked, sustained lowering of plasma cholesterol. Associated with the cholesterol lowering is a decrease in urinary and plasma levels of mevalonic acid, the end product of the HMG CoA reductase reaction. The target organ for inhibitors of HMG CoA reductase is the liver, the primary site of cholesterol biosynthesis. Both lovastatin and simvastatin are preferentially extracted by this organ.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗