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Testing of anti-atherogenic drugs and food components
on cell cultures: assessment of reliability.
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| Subject: |
Alimentos
(Investigacion cientifica) Alimentos (Analisis de casos) Alimentos (Composicion) Celulas (Investigacion cientifica) Celulas (Analisis de casos) |
| Author: | Jargin, Sergei V. |
| Pub Date: | 03/01/2010 |
| Publication: | Name: Puerto Rico Health Sciences Journal Publisher: Universidad de Puerto Rico, Recinto de Ciencias Medicas Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 Universidad de Puerto Rico, Recinto de Ciencias Medicas ISSN: 0738-0658 |
| Issue: | Date: March, 2010 Source Volume: 29 Source Issue: 1 |
| Geographic: | Geographic Name: Puerto Rico |
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| Accession Number: | 219519257 |
| Full Text: |
Atherogenesis involves multiple cell types interacting with each
other and with extracellular matrix (1). Therefore, results obtained on
a single cell type should be considered with caution when extrapolated
to the whole organism. A large series of studies, having become
internationally known in 1986 (2), has been continued until today by
Orekhov and co-workers. Cultures of smooth muscle cells from human aorta
were used as a testing model for evaluation of serum atherogenicity and
effectiveness of anti-atherogenic drugs and food components. The
following was reported: after 24 hours of cultivation with 40 % sera
from patients with coronary heart disease (CHD), the intracellular
cholesterol level in the cultured smooth muscle cells increased twofold
to fivefold; low density lipoproteins (LDL) from patients with CHD or
diabetes mellitus caused a twofold to fourfold intracellular cholesterol
elevation. On the contrary, the serum and LDL from healthy persons
failed to induce lipid accumulation (3-4). Furthermore, after 24 hours,
calcium antagonists (verapamil, nifedipine, darodipine, isradipine,
diltiazem, etc.) reduced cholesterol level in cultured cells, whereas
beta-blockers (propranolol, alprenolol, metoprolol, atenolol, pindolol,
and timolol) caused a 1.5- to twofold rise of cholesterol content in the
cells, cultured from an atherosclerotic plaque (5). In a handbook of
therapeutics (6) these data were summarized, and clinical
recommendations given on their basis. Among substances, demonstrating
anti-atherogenic effectiveness in vitro, the following were listed:
statins, trapidil, prostaglandin E2, dibutyryl cyclic AMP, calcium
channel blockers, lipoxygenase and acetylcholinesterase inhibitors,
carbacyclin; and among pro-atherogenic substances--beta-adrenergic
blockers, phenothiazines, oral hypoglycemics etc. The same data were
published in peer-reviewed journals (7-11). For example, clinical
recommendations were published in a pharmacological journal (12),
including dosages of drugs, calculated on the basis of cell culture
experiments: "To decrease atherogenic potential of serum and to
maintain it at a low level, verapamil should be administered at a dose
of 40mg 5 times daily with a 4- to 5-hour interval between doses"
(12). However, known action mechanisms of anti-atherogenic or
lipid-lowering agents include regulation of cholesterol synthesis, lipid
and lipoprotein metabolism in the liver, intestinal absorption, and
influence upon the endothelium-related factors (13-14). All these
targets are absent in cell cultures. Inflammatory mechanisms, influenced
by some anti-atherogenic agents (1), also cannot be reproduced in a cell
monoculture. In vivo, dependence between cellular cholesterol uptake and
atherogenesis is inverse rather than direct. For example, in familial
hypercholesterolemia caused by abnormality of LDL-receptors (which are
present also on the smooth muscle cells), inefficient clearance of LDL
from the serum results in hypercholesterolemia and predisposition to
atherosclerosis (15-16). Accordingly, if a drug reduces cholesterol
uptake by cells in vitro, it should be expected to cause blood
cholesterol elevation in vivo (17). Therefore, the conclusions and
recommendations regarding atherosclerosis treatment and prevention,
formulated on the basis of cell culture experiments discussed above, can
be disproven by reductio ad absurdum: pharmacologic agents with an
"anti-atherogenic" effect in cell cultures should be expected
to have a pro-atherogenic effect in vivo. Sergei V. Jargin Peoples' Friendship University of Russia Clementovski per 6-82; 115184 Moscow, Russia. Telephone and Fax: +7 495 9516788 Email: sjargin@mail.ru References (1.) Mundo-Sagardia JA, Figueroa Y, Altieri PI, Banchs HL, Escobales N, Crespo MJ. The atherosclerotic plaque. P R Health Sci J 2008;27:241-246. (2.) Chazov EI, Tertov VV, Orekhov AN, Lyakishev AA, Perova NV, Kurdanov KA, Khashimov KA, Novikov ID, Smirnov VN. Atherogenicity of blood serum from patients with coronary heart disease. Lancet 1986;2:595-598. (3.) Orekhov AN, Tertov VV, Pokrovsky SN, Adamova IYu, Martsenyuk ON, Lyakishev AA, Smirnov VN. Blood serum atherogenicity associated with coronary atherosclerosis. Evidence for nonlipid factor providing atherogenicity of low-density lipoproteins and an approach to its elimination. Circ Res 1988;62:421-429. (5.) Orekhov AN, Baldenkov GN, Tertov VV, Ryong LH, Kozlov SG, Lya kishev AA, Tkachuk VA, Ruda MYa, Smirnov VN. Cardiovascular drugs and atherosclerosis: effects of calcium antagonists, beta-blockers, and nitrates on atherosclerotic characteristics of human aortic cells. J Cardiovasc Pharmacol 1988;12(Suppl 6):S66-S68. (6.) Pivovarova EM. Treatment of Atherosclerosis (In Russian). In: Clinical Angiology. (Pokrovsky AV ed), Moscow; Meditsina, v. 2, 2004, p. 712-714. (7.) Orekhov AN. In vitro models of anti-atherosclerotic effects of cardiovascular drugs. Am J Cardiol 1990;66:23I-28I. (8.) Orekhov AN, Andrianova IV, Rekhter MD, Tertov VV, Andreeva ER, Ragimov SE, Mironov AA. Beta-blockers: propranolol, metoprolol, atenolol, pindolol, alprenolol and timolol, manifest atherogenicity on in vitro, ex vivo and in vivo models. Elimination of propranolol atherogenic effects by papaverine. Atherosclerosis 1992;95:77-85. (9.) Orekhov AN, Tertov VV, Pivovarova EM. The effects of antihypertensive agents on atherosclerosis-related parameters of human aorta intimal cells. Cardiology 1998;89:111-118. (10.) Orekhov AN, Tertov VV, Kudryashov SA, Khashimov KhA, Smirnov VN. Primary culture of human aortic intima cells as a model for testing antiatherosclerotic drugs. Effects of cyclic AMP, prostaglandins, calcium antagonists, antioxidants, and lipid-lowering agents. Atherosclerosis 1986;60:101-110. (11.) Tertov VV, Orekhov AN, Kudryashov SA, Klibanov AL, Ivanov NN, Torchilin VP, Smirnov VN. Cyclic nucleotides and atherosclerosis: studies in primary culture of human aortic cells. Exp Mol Pathol 1987;47:377-389. (12.) Orekhov AN, Pivovarova EM, Sobenin IA, Yakushkin VV, Tertov VV. Use of cell culture for optimisation of direct antiatherogenic therapy with verapamil. Drugs 1992;44:105-110. (13.) Mosca L. Hyperlipidemia. In: Cardiology, 7th edition. (Crawford MN, DiMarco JP, Paulus WJ, et al.), Edinburgh; Mosby, 2004: p. 73-90. (14.) Kraemer BF. Miller JW. Dyslipidemias In Clinical Pharmacology, 4th Edition. (Carruthers SG, Hoffman BB, Melmon KL, Nierenberg DW), New York; McGrow-Hill, 2000: p. 552-580. (15.) Cotran RS, Kumar V, Collins T. Robbins' Pathologic Basis of Disease, Philadelphia; W.B. Saunders Co., 1999: p. 150-153, 418-509. (16.) Marais AD. Familial hypercholesterolaemia. Clin Biochem Rev 2004; 25:49-68. (17.) Jargin SV. Cell culture as a testing system for anti-atherogenic substances: a brief communication. Accessed on 04.11.2009. Available at: URL: http://www.actapharmasciencia.org/archive.asp. Acta Pharm Sci 2008;50:237-240. Reply In this letter, Dr. Jargin raises the important issue on whether studies from simple cellular models can be used to model the response of organs, systems, or the body to anti-atherogenic treatments. The use of cellular systems in pharmacological studies is critical in the initial evaluation of drugs. However, their use to predict the response of the body to a given agent is limited as the author correctly indicates. The determination of the concentration of a drug inhibiting a given physiological pathway by 50% (IC50) in a cellular system bears very little connection to the response of complex units (i.e. body) where besides the direct cellular response to the drug there is an interplay between tissues or organs affecting the agent. A critical component in this issue would be the excretion and/or metabolic routes of the drug that affects its pharmacokinetics in vivo. For this reason, caution must be exerted when determinations of IC50 obtained in cellular systems are used to predict the response of the body system to a given drug. Also, the response of cellular systems to an agent affecting the transport across the plasma membrane of a given substance could have opposite effects in the cell and the organism. For example, low transport of cholesterol into cells would be expected to generate hypercholesterolemia and atherosclerosis (1-3). Similarly, treatments with steroids that reduce glucose uptake into cells are well known to be diabetogenic (4). For these reasons, the development of pharmacological treatments must be in the end, based on in vivo animal studies followed by carefully designed clinical trials. Nelson Escobales, Ph D Department of Physiology University of Puerto Rico School of Medicine References (1.) Cotran RS, Kumar V, Collins T. Robbins' Pathologic Basis of Disease, Philadelphia; W.B. Saunders Co., 1999: p. 150-153, 418-509. (2.) Marais AD. Familial hypercholesterolaemia. Clin Biochem Rev 2004; 25:49-68. (3.) Jargin SV. Cell culture as a testing system for anti-atherogenic substances: a brief communication. Accessed on 04.11.2009. Available at: URL: http://www.actapharmasciencia.org/archive.asp. Acta Pharm Sci 2008;50:237-240. (4.) van Raalte DH, Ouwens DM, Diamant M. Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest 2009;39:81-93. |
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