Stimulation of rat liver 3-hydroxy-3-methylglutaryl-coenzyme a reductase activity by o,p′-DDD

Stacpoole, Peter W.; Varnado, Carol E.; Island, Donald P.

doi:10.1016/0006-2952(82)90474-9

Cited by 14 publications

(13 citation statements)

References 24 publications

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“… 17 However, previous studies suggest that hypercholesterolemia might be dependent on an increased cholesterol synthesis related to the mitotane-induced up-regulation of 3-hydroxy-3-methyl-glutaryl-coenzyme A-reductase activity. 18 , 19…”

Section: Mitotane - Mechanisms Of Actionmentioning

confidence: 99%

Role of Mitotane in Adrenocortical Carcinoma – Review and State of the art

Paragliola

Torino

Papi

et al. 2018

European Endocrinology

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Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine tumour deriving from the adrenal cortex. A correct therapeutic strategy requires a multidisciplinary approach between endocrinologist, surgeon and oncologist. Surgery is the mainstay treatment in ACC while mitotane, deriving from the insecticide dichloro-diphenyl-trichloro-ethane, is the main base of the medical treatment of ACC in consideration of its adrenocytolitic activity. However, the use of mitotane as adjuvant therapy is still controversial, also in consideration of the retrospective nature of several studies. A prospective randomised trial (ADIUVO), recruiting patients with low-intermediate risk of recurrence, is evaluating the utility of adjuvant treatment with mitotane in this setting. The therapeutic response is observed with plasma levels of mitotane >14 mg/L. However, the major difficulty in the management of mitotane treatment is related to side effects and to the risk of toxicity, which is related to plasmatic levels >20 mg/L, that is considered the upper limit of the therapeutic window. Mitotane therapy results in adrenal insufficiency, and glucocorticoid replacement therapy has to be administered at higher doses than those used in other aetiologies of primary adrenal insufficiency. Furthermore, other endocrine side effects related to mitotane should be considered, in particular on thyroid hormone and testosterone metabolism. Waiting for new medical strategies on molecular targets, it will be mandatory to optimise the current knowledge by prospective trials and, in consideration of the rarity of the disease, collaborative studies between endocrinologists and oncologists are necessary.

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Section: Mitotane - Mechanisms Of Actionmentioning

confidence: 99%

Role of Mitotane in Adrenocortical Carcinoma – Review and State of the art

Paragliola

Torino

Papi

et al. 2018

European Endocrinology

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“…Isolated, morphologically intact, hepatic parenchymal cells were obtained in high yield by a modification (28) of the technique of Berry and Friend (31). Livers were perfused in situ with an oxygenated, calcium-free, Krebs-Henseleit original Ringer bicarbonate buffer (pH 7.4) containing 0.05% collagenase.…”

Section: Liver Cell Isolation and Incubationmentioning

confidence: 99%

“…Livers were perfused in situ with an oxygenated, calcium-free, Krebs-Henseleit original Ringer bicarbonate buffer (pH 7.4) containing 0.05% collagenase. After a 30-45 min perfusion, isolated cells were separated from debris, washed, and resuspended in fresh enzyme-free medium, as previously described (16,28 …”

Section: Liver Cell Isolation and Incubationmentioning

confidence: 99%

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Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

Stacpoole¹,

Harwood²,

Varnado³

1983

J. Clin. Invest.

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A B S T R A C T Dichloroacetate (DCA) markedly reduces circulating cholesterol levels in animals and in patients with combined hyperlipoproteinemia or homozygous familial hypercholesterolemia (FH). To investigate the mechanism of its cholesterol-lowering action, we studied the effects of DCA and its hepatic metabolites, glyoxylate and oxalate, on the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) obtained from livers of healthy, reverse light-cycled rats. Oral administration of DCA for 4 d decreased HMG CoA reductase activity 46% at a dose of 50 mg/kg per d, and 82% at a dose of 100 mg/kg per d. A 24% decrease in reductase activity was observed as early as 1 h after a single dose of 50 mg/ kg DCA. The inhibitory effect of the drug was due to a fall in both expressed enzyme activity and the total number of reductase molecules present. DCA also decreased reductase activity when added to suspensions of isolated hepatocytes. With chronic administration, DCA inhibited 3H20 incorporation into cholesterol by 38% and into triglycerides by 52%. When liver microsomes were incubated with DCA, the pattern of inhibition of reductase activity was noncompetitive for both HMG CoA (inhibition constant [Ki] 11.8 mM) and NADPH (K; 11.6 mM). Inhibition by glyoxylate was also noncompetitive for both HMG CoA (K1 1.2 mM) and NADPH (K1 2.7 mM). Oxalate inhibited enzyme activity only at nonsaturating concentrations of NADPH (K, 5.6 mM Department of Medicine, College ylene glycol, all of which can form glyoxylate, also inhibited reductase activity. Using solubilized and 60-fold purified HMG CoA reductase, we found that the inhibitory effect of glyoxylate was reversible. Furthermore, the inhibition by glyoxylate was an effect exerted on the reductase itself, rather than on its regulatory enzymes, reductase kinase and reductase phosphatase. We conclude that the cholesterol-lowering effect of DCA is mediated, at least in part, by inhibition of endogenous cholesterol synthesis. The probable mechanisms are by inhibition of expressed reductase activity by DCA per se and by conversion of DCA to an active metabolite, glyoxylate, which noncompetitively inhibits HMG CoA reductase. These studies thus identify a new class of pharmacological agents that may prove useful in regulating cholesterol synthesis and circulating cholesterol levels in man.

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“…The use of mitotane is associated with multiple adverse effects, including hyperlipidemia. Mitotane increases the levels of low-density lipoprotein cholesterol (LDL-c) via the stimulation of hydroxymethylglutarate-coenzyme A (HMG-CoA) reductase (the rate-limiting enzyme in cholesterol synthesis) [2–7]. Lipid changes in association with mitotane have been reported in small number of subjects.…”

Section: Introductionmentioning

confidence: 99%

Mitotane-Induced Hyperlipidemia: A Retrospective Cohort Study

Shawa

Denız

Bazerbashi

et al. 2013

International Journal of Endocrinology

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Limited data are available about mitotane-nduced hyperlipidemia. We retrospectively analyzed lipid data in 38 patients with adrenocortical carcinoma (ACC) who received mitotane therapy with emphasis on HDL cholesterol (HDL-c) and clinical predictors of lipid changes. At baseline, the mean levels of HDL-c, LDL-c, and triglycerides were 53.3 mg/dL, 114.4 mg/dL, and 149 mg/dL, respectively. HDL-c, LDL-c, and triglyceride concentrations significantly increased with mitotane therapy to a mean HDL peak (HDL-P) of 86.3 mg/dL (P < 0.001), a mean LDL peak of 160.1 mg/dL (P < 0.001), and a mean triglyceride peak (Tg-P) of 216.7 mg/dL (P = 0.042). HDL-P positively correlated with mitotane concentration (r = 0.52, P < 0.001), while LDL-P levels and Tg-P did not. Gender, body mass index, cortisol overproduction, baseline levels of HDL-c, and triglyceride did not predict change in HDL-c. Similar changes were noticed in subgroup analysis after excluding patients who were using lipid-lowering agents. In conclusion, in ACC patients, mitotane caused significant increases in HDL-c that may counteract the deleterious atherosclerotic effects of LDL-c and Tg rise. Understanding the mechanism of HDL change may lead to the discovery of novel HDL-c-elevating drugs.

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Stimulation of rat liver 3-hydroxy-3-methylglutaryl-coenzyme a reductase activity by o,p′-DDD

Cited by 14 publications

References 24 publications

Role of Mitotane in Adrenocortical Carcinoma – Review and State of the art

Role of Mitotane in Adrenocortical Carcinoma – Review and State of the art

Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

Mitotane-Induced Hyperlipidemia: A Retrospective Cohort Study

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