Egypt. J. Histol. Vol 31, No.2, Dec. 2008: 312 - 320
(ISSN: 1110 - 0559)
Original Article
Effect of Simvastatin on the Exocrine Part of the Pancreas in Adult Albino
Rat and the Possible Protective Role of Coenzyme Q10: A Light and
Electron Microscopic Study
Nafisa A. El-Bakary and Amany M. Mousa
Histology Department, Faculty of Medicine, Tanta University
ABSTRACT
Introduction: The statins represent the drugs of choice for treatment of hypercholesterolaemia. Because of the common
use of statin's (including simvastatin), both physicians and patients have demonstrated valid concerns about the safety
associated with the use of such medications.
Aim of the Work: This work was performed to study the effect of simvastatin on the exocrine part of the pancreas and
to evaluate the possible protective role of Coenzyme Q10 (CoQIO).
Material and Methods: The present study was carried out on 35 adult male albino rats which were divided into; group
I (control group), group II (given 1.44 mg of simvastatm once daily for 12 weeks) and group III (given simvastatin in
the same dose concomitantly with 3.6 mg of CoQIO once daily for the same period). The specimens were prepared for
light and electron microscopic examination.
Results: Sections of simvastatin-treated rats showed morphological changes in acinar cells in the form of pyknotic
nuclei, cytoplasmic vacuolation, abnormal shape of acini, congestion of blood vessels and widening of interstitial tissue.
By Verhoeff's Van Gieson's stain, dissolution of elastic laminae was detected in some blood vessels. Ultrastructurally,
there were variation of electron density of zymogen granules, dilation of both RER and perinuclear space, large vacuoles
and damaged mitochondria in some acinar cells. The above findings were less prominent in animals treated with both
simvastatin and CoQIO.
Conclusion: Simvastatin has a harmful effect on the exocrine part of the pancreas and it is advisable that patients
receiving simvastatin could use CoQIO to minimize its side effects.
Key Words: Simvastatin, coenzyme Q10, exocrine
pancreas
Corresponding Author: Nafisa A. Elbakary
Tel.:0109171524
E-mail: [email protected]
INTRODUCTION
The pancreas is one of the hidden organs in the body
due to its posterior location in the upper abdomen and is
therefore impossible to palpate clinically. Diseases that
impair its function evoke signs or symptoms only when
far advanced, because there is such a large reserve of
both exocrine and endocrine functions1.
consumption, gall stones, trauma or surgical procedures,
hyperlipidaemia, infection and chronic hypercalcaemia3.
However, drugs are related to the etiology of pancreatitis
and more than 260 drugs have been implicated so far as
possible causes or co-factors in pancreatitis45. There is
a growing evidence that statins of all kinds seem to be
responsible for many such cases6.
Pancreatitis is a clinical condition, whose incidence
has been increasing over recent years. It is a disease
of variable severity in which some patients experience
mild, self-limited attacks while others manifest a severe,
highly morbid, and frequently lethal attacks. The events
that regulate the severity of pancreatitis are, for the most
part, unknown2.
for
Statins (hydroxymethylglutaryl-coenzyme A (HMGCoA) reductase inhibitors) are the drugs of first choice for
the treatment of hypercholesterolaemia in order to prevent
or slow the progression of coronary heart disease7. They
are effective in lowering plasma total cholesterol and lowdensity lipoprotein levels by inhibiting the enzyme HMG
CoA reductase which is the rate-limiting enzyme of the
mevalonate pathway of cholesterol synthesis8. Moreover,
statins have been described for a wide variety of clinical
Many etiological risk factors have been reported
pancreatitis, including excessive alcoholic
30(1115-2008)
312
Nafisa A.El-Bakaty and Amany M.Mousa
conditions due to their action as anti-inflammatory,
antithrombotic, neuroprotective and chemotherapeutic
agents9.
of simvastatin and 3.6 mg of CoQIO (each dissolved in 2
ml of its vehicle) orally once daily for 12 weeks. The dose
of CoQIO was equivalent to the human therapeutic dose
of 200 mg daily15. Coenzyme Q 10 was manufactured
by Global Napi Pharmaceutical Company in the form of
capsules of 30mg.
Simvastatin (Zocor) is a chemically modified
derivative of statins. The drug is administered in
the form of an inactive lactone that is enzymatically
hydrolyzed after ingestion to produce the active agent.
It is lipophilic in nature and can enter endothelial cells
by passive diffusion more efficiently than hydrophilic
statins. It is then bound by serum proteins with a limited
bioavailability and finally metabolized by the liver where
about 80% of the drug is retained1011.
At the expected time, the animals were anaesthetized
with diethyl ether and perfused intracardially with 4%
paraformaldehyde in 0.1 M phosphate buffered solution
(PH 7.4) containing 2.5 % glutaraldehyde solution.
The pancreas was dissected out and some specimens
were processed for light microscopy and stained with
haematoxylin and eosin as well as Verhoeff's Van Gieson's
stains16. Parallel tissue specimens were processed for
electron microscopy by immediate immersion for two
hours in 2.5% glutaraldehyde fixative based on 0.1 M
phosphate buffer (pH 7.4). They were then washed three
times (5 minutes each) with phosphate buffer followed
by postfixation in 1 % phosphate buffered osmium
tetroxide for one hour. After dehydration in ascending
grades of ethyl alcohol, the specimens were embedded in
Epon-araldite mixture. Ultrathin sections were cut with
ultramicrotome using a diamond knife and were stained
with uranyl acetate and lead citrate to be examined by the
transmission electron microscope17 at Faculty of Science,
Ain-Shams University.
Coenzyme Q10 (CoQIO) is a vitamin-like fat-soluble
antioxidant found everywhere in the body. This substance
is, by nature, present in most human cells except red blood
cells and eye lens cells, where there is no mitochondria,
and is responsible for the production of the body's own
energy. It was reported that ninety-five percent of all the
human body's energy requirements (ATP) is converted
with the aid of CoQIO. Therefore, organs with the highest
energy requirements such as the heart, liver and pancreas
have the highest CoQIO concentrations12,13.
This work aimed to study the histological changes
that may occur in the exocrine pancreas of adult albino
rat after treatment with simvastatin and the possible
protective effect of Coenzyme Q10 using light and
electron microscopy.
RESULTS
MATERIAL AND METHODS
Light microscopic results:
Group I:
Histological examination of specimens from the
control animals showed normal histological structure
of the pancreas consisting of the exocrine component
(formed of closely packed secretory acini with narrow
lumina) and the endocrine part (formed of the islets
of Langerhans which were scattered throughout the
exocrine tissue) (Fig. 1). The pancreatic acini consisted
of pyramidal cells with rounded pale-stained nuclei
surrounded by basophilic cytoplasm and the apices of the
cells were packed with eosinophilic secretory granules
(Fig. 2). Verhoeff's Van Gieson's stained-sections showed
intact blood vessels and the wall of arterioles showed a
distinct well defined internal elastic lamina (Fig. 3).
This study was carried out on 35 adult male albino
rats ranging in weight from 150 - 200 grams each. All
animals were kept in clean ventilated cages under
similar environmental conditions and were fed the same
laboratory diet. They were divided into three groups:
Group I (control group): Included 15 rats which
were further subdivided into 3 subgroups. Subgroup 1
(negative control animals) included 5 animals being kept
without any treatment. Subgroup 2 (positive control for
simvastatin-treated animals) included 5 animals given
2 ml of 0.5% carboxymethyl cellulose (the vehicle for
simvastatin) orally once daily for 12 weeks. Subgroup
3 (positive control for animals treated with simvastatin
and CoQIO) included 5 animals given 2 ml of 0.5%
carboxymethyl cellulose and 2 ml of soybean oil (The
vehicle for CoQIO) orally once daily for 12 weeks.
Group II:
Examination of specimens obtained from simvastatintreated animals showed focal lesions affecting the
exocrine part of the pancreas. Some acinar cells showed
pyknotic nuclei, abnormal shape of acini and disturbance
of the normal architecture of the pancreas (Fig. 4).
Few specimens showed severely damaged acini which
appeared containing large vacuoles (Fig. 5). Other parts
showed hemorrhagic areas with wide interstitial tissue
(Fig. 6). Congestion and detached endothelial lining of
the interstitial blood vessels were also observed in some
focal areas (Fig. 7). By Verhoeff's Van Gieson's stain,
Group II: Included 10 animals, each received 1.44 mg
of simvastatin dissolved in 2 ml of its vehicle orally
once daily for 12 weeks. This dose was equivalent to the
human high therapeutic dose of 80 mg daily which can be
used in severe and resistant cases14. Simvastatin (Zocor)
was manufactured by Merk Sharp Company in the form
of tablets of 20 mg.
Group III: Included 10 animals, each received 1.44_mg
313
Effect of Simvastafin <m the Exocrine Part of the Pancreas in Vdull Albino U:u
destroyed walls of the blood vessels and dissolution of
elastic laminae were detected (Fig. X).
Group III:
Most of the specimens obtained from animals given
simvastatin and CoQIO revealed normal pancreatic
architecture (fig. 9). However, some blood vessels
appeared mildly congested and widening of interstitial
tissue was also observed (Fig. 10). VerhoelTs Van
Gieson's stained-sections showed intact vessel walls in
most specimens (Fig. 11).
Election microscopic results:
Group I:
Examination of specimens obtained from the control
animals showed the exocrine acinar cells containing
rounded nuclei with dispersed chromatin, surrounded
by numerous cisternae of RER. Their apical poles were
occupied by numerous electron-dense secretory granules
of variable sizes. The lumina of the acini were narrow
and contained microvilli (Fig. 12).
timm
*
1
.*>,
m
•
Fig. 2: A photomicrograph of rat pancreas from the control group showing
the pancreatic acini composed of pyramidal shaped cells with rounded pale
stained nuclei (—>) surrounded by basophilic cytoplasm. The apices of the
cells arc packed with eosinophilic granules.
H&E.Mic.Mau. X 1000.
Group II:
Specimens obtained from simvaslatin-treatcd animals
revealed dilation of both RER and perinuclear space in
some acinar cells (Fig. 13). Other acinar cells showed
large vacuoles that appeared either empty or containing
librillar materials (Figs. 14,15). Secondary lysosomes
and damaged mitochondria were also observed (Fig. 15).
Some acinar lumina were dilated and showed effacement
and damage of microvilli (Fig. 16). As regards /.ymogen
granules, loss or variation of electron density, peripheral
dissolution and basally located granules were observed
in many acinar cells (Figs. 17.18,19). Widening of
interstitial tissue was also noticed (Fig. 19).
C r o u p III:
Specimens obtained from animals of group 111 showed
mild focal ultrastructural changes manifested by dilated
RER and few damaged mitochondria in some acinar cells
(Fig. 20).
Fig. 1: A photomicrograph of ral pancreas from the control group
showing the closely packed pancreatic acini and the pale-stained islets
of Langerhans (— •) scattered inbetween them.
H&E, Mic.Maa. X 20(),
Fig. 3: A photomicrograph of ral pancreas from the control group snowing
intact blood vessels, distinct well defined internal elastic lamina of an
arleriolc ( •).
Verhoeff's Van Gieson's stain. Mic.Mag. X 40().
Fig. 4: A photomicrograph ol'nu pancreas from siuivastatin-trcatcd group
(Group III showing pyknotic nuclei of some acinar cells {—») and focal
disturbance of acinar architecture,
H&i . MicMfig. X I "00
314
Nafisa A.EI-Bukary and Amany M.Mousa
Fig. 5: A photomicrograph of rat pancreas from group II showing severely
damaged vacuolated acini (->).
H&E, Mic.Mag. X 1000.
Fig. 8: A photomicrograph of rat pancreas from group II showing destroyed
walls of blood vessels and focal dissolution of elastic lamina (-*).
VevhoelTs Van Gicson's slain. Mic.Mag. X 400.
/
~j&
Fig. 6: A photomicrograph of rat pancreas from group 11 showing a wide
hemorrhagic area in the interstitial tissue (Mg). Notice the presence of
vacuolation in some acinar cells (—>).
H&E, MicMae. X 400.
r
Fig. 9: A photomicrograph of ral pancreas from group III (treated with
simvaslatin and CoQIO) showing nearly normal pancreatic architecture.
Notice the presence of pyknotic nuclei (—►) in some acinar cells
H&E. Mic.Mag. X 400.
JO®
■
i
V
'"'•
/
i
Fig, 7: A photomicrograph of nil pancreas from group II showing
congestion of a blood vessel (V): and detached endolhclial lining of
another ( -«)• Notice wide interstitial tissue (*).
H&E, Mic.Mag. X 200.
Fig. It): A photomicrograph of ral pancreas from group III showing mild
congestion of a blood vessel (V) and wide interstitial tissue (*).
315
H&E. Mic.Mag. X 200.
Effect of Simvastatin on the Exocrine Part of (be Pancreas in Adult Vlbino Rat
Fig. 11: A photomicrograph of rat pancreas from group III showing intaci
vessel walls ( —).
VerhoefPs Van Giesoii's stain, Mic.Mag. x 400.
Fig. 14: An electron micrograph of rat pancreas from group u showing
large vacuoles ( —), one of them contains fibrillar materials ( •).
MicMaa. X 6G00.
IT
Fig. 12: An electron micrograph ofofrat pancreas from the control group
showing exocrine acinar cells containing a rounded euchromattc nucleus
(Nl. surrounded by numerous cisternae of RER, Their apical poles are
occupied by numerous electron dense secretorj granules of variable sizes.
Notice the narrow acinar lumen (L) containing microvilli.
Mic.Mag, X 5000
Fig. 15: An electron micrograph of ral pancreas from group II
showing huge vacuoles ( —). secondary lysosomes (>) and damaged
mitochondria! m).
Mic.Mag. X 6000.
Fig. 13: An electron micrograph of rat pancreas from group II showing
dilation of both RER ( •) and pcritutclcar space ( I in some acinar cells.
Mic.Mag \ 7500
Fig. 16: \n electron micrograph at rat pancreas from group II showing
dilated acinar lumen (L). ell'accment and destruction ol microvilli I •)
Mic.Mag, X 7500.
3I6
Nafisa A.El-Bakary ami Amany M.Mousa
Fig. 17: An electron micrograph of rat pancreas from group 11 showing
loss or variation of electron density and peripheral dissolution of zymogcn
granules (—>).
Mic.Mae. X 7500.
Fig. 20: An electron micrograph of rat pancreas from group III (treated
with simvastalin and CoQIO) showing a hinucleated acinar cell
containing dilated RER and Few damaged mitochondria (in).
Mic.Mag. X 7500.
DISCUSSION
This work revealed that treatment with a high dose
of simvastatin induced histological and ultraslructural
changes in the exocrine pancreas. In this regard, it was
reported that although statins are generally well tolerated.
pancreatitis has been reported in some cases treated with
atorvastatin, fiuvastatin, lovastatin and simvastatin and
in all of these cases, other causes of the disease were
ruled out18. Although lew data exist about the incidence
of drug-induced pancreatitis in the general population.
some cases of pancreatitis are thought to be drug-induced
to some degree. It was reported that when ethanol abuse,
smoking, and biliary disease are ruled out as aetiologies
for pancreatitis, the possibility of drug-induced disease
should be investigated"11".
Fig. 18: An electron micrograph of rat pancreas from group II showing
basally located zymogen granules. Notice dilated RER (-*).
Mic.Mag. X 7500.
Fig. 19: An electron micrograph of rat pancreas from group II showing
basally located zymogcn granules in an acinar cell and wide interstitial
tissue (*).
MicMag. X4000.
317
In this research, light microscopic examination of the
pancreas of simvastatin-treated rats revealed local acinar
damage in the form of abnormal acinar shape, cytoplasmic
vacuolation and pyknotic nuclei of some acinar cells with
subsequent loss of the known pancreatic architecture.
These findings indicated that the pancreatic acini are a
target for statins. Similar results were also previously
reported by some authors 20 and were described as acute
pancreatitis.
In line with these findings, the present study showed
ultrastructural lesions of acinar cells in specimens of
simvastatin-treated animals such as dilation of RER,
swollen and damaged mitochondria as well as large
vacuolcs which appeared either empty or containing
filamentous materials. In addition, dilated acinar lumina
and loss or elTacement of microvilli were observed in
some specimens. The same findings were previously
recorded by other investigators and were described as
acinar cell necrosis21.
In ihis regard, some scientists
reported
that a
Effect of Simvastatin on the Exocrine Part of the Pancreas in Adult Albino Rat
membrane-bound system through which secretory and
lysosomal proteins travel in a vectorial fashion is essential
for the preserved integrity of pancreatic acinar cells. This
system is composed of an ordered array of compartments
such as RER, Golgi complex, lysosomes, and secretory
granules. However, in acute pancreatitis the final steps of
this transport system seem to be disturbed. The formation
of enlarged secretory vacuoles containing lysosomal
and digestive enzymes is paralleled by the activation
of lysosomes and degradation of cellular organelles
in autophagosomes. This process represents the initial
stage for acinar cell destruction and the development of
pancreatitis22. Other pathologists confirmed the same idea
and reported that necrosis of pancreatic acinar cells was
associated with specific intracellular vacuoles that arise
from zymogen granules and contain large amounts of
filamentous materials which were proved to be pancreatic
digestive enzymes especially alpha amylase which is able
to digest and disrupt the surrounding organelles23.
rodents, numerous chemical toxicants have been
identified for exocrine pancreas and, to a lesser degree,
the endocrine component27.
In the present work, vascular lesions in the form of
endothelial detachment of small blood vessels, dissolution
of vascular wall elastic laminae and damaged vessels wall
with subsequent extravasation of blood elements were
common findings in specimens of simvastatin-treated
animals. Moreover, widening of the interstitial tissue and
interstitial hemorrhage were also frequent observations.
In this regad, it was reported that chemical mediators such
as free radicals and platelet activating factors (PAF) which
are produced by vascular damage and thrombosis may
accelerate the activation of zymogen protease in acinar
cells leading to hemorrhagic pancreatitis21. In addition,
similar vascular lesions were previously observed by
other investigators who suggested that the elastic laminae
were markedly affected in pancreatitis and explained this
as an early participation of elastase in the production of
tissue damage in pancreatitis as well as to a primary role
for elastic tissue injury in the vascular alterations leading
to hemorrhage and tissue necrosis through ischaemia28.
As regards zymogen granules, the present study
showed loss or variation of electron density, peripheral
dissolution and basal location of zymogen granules in
some acinar cells. Some acini appeared degranulated
while others retained their granular content. The basally
located zymogen granules were also recorded by other
investigators who stated that the acinar cells adjacent
to fat necrosis release their granules by undirected
basolateral extrusion. They suggested that one of the
basic defects in pancreatitis is the uncontrolled release of
enzymes from peripheral acinar cells into the interstitial
space which, in turn, presumably by the action of lipase,
leads to autodigestive fat necrosis24.
In this study, it was observed that coadministration
of CoQIO with simvastatin was effective in decreasing
the severity of most histological changes observed after
administration of simvastatin alone. This was coincided
with other studies which reported that statin toxicity on
human lymphocyts in tissue culture could be reversed by
the addition of CoQIO29. Also, the apoptosis which can
be induced by statins in cultured myoblasts was inhibited
by CoQIO30. It was reported that the enzyme HMG-CoA
reductase is involved in the biosynthesis of CoQIO in
addition to its involvement in cholesterol synthesis.
Therefore, HMG-CoA reductase inhibitors (statins)
have been shown to decrease the levels of CoQIO in a
dose dependent manner, which could be corrected by
coadministration of Coenzyme Q1013.
It is generally believed that the earliest events
in pancreatitis occur within acinar cells leading to
inflammation and general tissue disruption. Other
processes, such as recruitment of inflammatory cells
and generation of inflammatory mediators, are believed
to occur subsequent to acinar cell injury, and these
"downstream" events are believed to influence the
severity of the disease2. At the cellular level, cell damage
is believed to be initiated by the activation of digestive
enzymes within acinar cells3. It was reported that acute
pancreatitis disrupts posttranslational protein processing
and traffic in the secretory pathway, and zymogens
become activated in the acinar cell25. Many researchers
attributed the degenerative changes in pancreatitis to
autodigestion of the pancreatic parenchyma by activated
pancreatic enzymes especially trypsin1. However, it was
stated that several other mechanisms were suggested
for drug-induced pancreatitis including pancreatic duct
constriction, immunosupression, cytotoxic osmotic
pressure, metabolic effects, arteriolar thrombosis, direct
cellular toxicity and hepatic involvement26.
It could be concluded that simvastatin induced
histological changes in rat pancreas similar to the lesions
of pancreatitis. Also, CoQIO could act as a protective
agent against simvastatin-induced pancreatitis in rats. It
is advisable that patients receiving simvastatin could use
CoQIO to minimize its side effects.
REFERENCES
1.
2.
3.
It was recorded that the pancreas of mammals is
capable of biotransforming drugs and other chemicals
and is subjected to toxic injury by the resultant reactive
metabolites. In case of experimental animals, especially
318
Cotran RS, Kumar V and Collins T (1999): Robbins pathologic
bases of disease. 6th ed. Saunders: Philadelphia.?. 904.
Bhatia M (2004): Apoptosis of pancreatic acinar cells in
acute pancreatitis: Is it good or bad? J. Cell. Mol. Mcd.
Jul-Sep; 8 (3): 402-409.
Kowalik AS, Johnson CL, Chadi SA, Weston JY, Fa/.io EN
and Pin CL (2007): Mice lacking the transcription factor Mistl
exhibit an altered stress response and increased sensitivity to
cacrulcin-induced pancreatitis. Am.J.Physiol.Gastrointest.Liver
Physiol. Apr, 292 (4): G1123-G1132.
Nafisa AEl-Bakary and Amany M.Mousa
4.
5.
6.
7.
Anagnostopoulos GK, Tsiakos S, Margantinis G, Kostopoulos
P and Arvanitidis D (2003): Acute pancreatitis due to pravastatin
therapy. JOP May; 4 (3): 129-132.
Battillocchi B, Diana M, Dandolo R, Stefanini S, D'Amore L
and Negro P(2002): [Drug-induced acute pancreatitis: A personal
contribution]. Chir.Ital. Sep-Oct; 54 (5): 605-612.
Antonopoulos S, Mikros S, Kokkoris S, Protopsaltis J, Filioti
K, Karamanolis D and Giannoulis G (2005): A case of acute
pancreatitis possibly associated with combined salicylate and
simvastatin treatment. JOP. May; 6 (3): 264-268.
17.
Bozzola JJ and Russell LD (1999): Electron microscopy:
Principles and techniques for biologists. 2nd ed. Jones & Bartlett
Publishing Co.P. 16.
18.
Andersen V, Sonne J and Andersen M (2001): Spontaneous
reports on drug-induced pancreatitis in Denmark from 1968 to
1999. Eur. J. Clin.Pharmacol. Sep; 57 (6-7): 517-521.
19. Underwood TW and FryeCB (1993): Drug-induced pancreatitis.
Clin.Pharm. Jun; 12 (6): 440-448.
20.
Frisinghelli A and Mafrici A (2007): Regression or reduction in
progression of atherosclerosis and avoidance of coronary events,
with lovastatin in patients with or at high risk of cardiovascular
disease: A review. Clin. Drug Investig; 27 (9): 591-604.
21.
8.
Mo H and Elson CE (2004): Studies of the isoprenoid-mediated
inhibition of mevalonate synthesis applied to cancer chemotherapy
and chemoprevention. Exp. Biol. Med. M ; 229 (7): 567-585.
9. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P and
Lechat P (2003): Differential effects of lipid-lowering therapies
on stroke prevention: A meta-analysis of randomized trials. Arch.
Intern.Med. Mar 24; 163 (6): 669-676.
10. Stancu C and Sima A (2001): Statins: Mechanism of action and
effects. J. Cell. Mol. Med. Oct-Dec; 5 (4): 378-387.
11. Dulak J and Jozkowicz A (2005): Anti-angiogenic and antiinflammatory effects of statins: Relevance to anti-cancer therapy.
Curr. Cancer. Drug Targets Dec; 5 (8): 579-594.
12. Shindo Y, Witt E, Han D, Epstein W and Packer L (1994):
Enzymic and non-enzymic antioxidants in epidermis and dermis
of human skin. J. Invest. Dermatol. Jan; 102 (1): 122-124.
22.
23.
24.
25.
Aho HJ, Nevalainen TJ, Havia VT, Heinonen RJ and Aho
AJ (1982): Human acute pancreatitis: A light and electron
microscopic study. Acta Pathol. Microbiol. Immunol. Scand.fA]
Sep; 90 (5): 367-373.
Takano S, Kimura T, Kawabuchi M, Yamaguchi H, Khvjo
M and Nawata H (1994): Ultrastructural study of the effects of
stress on the pancreas in rats. Pancreas Mar; 9 (2): 249-257.
WillemerS and AdlerG (1991): Mechanism of acute pancreatitis.
Cellular and subcellular events. Int. J.Pancreatol. 9: 21-30.
Xia YF (1993): [An electron microscopical study on the
pathogenesis of taurocholate-induced acute pancreatitis].
Zhonghua Bing Li Xue Za Zhi. Feb; 22 (1): 30-32.
Kloppel G, Dreyer T, Willemer S, Kern HF and Adler G
(1986): Human acute pancreatitis: Its pathogenesis in the light of
immunocytochernical and ultrastructural findings in acinar cells.
Virchows Arch.A Pathol.Anat.Histopathol. ;409 (6): 791-803.
De Lisle RC (2005): Altered posttranslational processing of
glycoproteins in ceralem-induced pancreatitis. Exp. Cell Res.
Aug 1; 308(1): 101-113.
26. Wilmink T and Frick TW (1996): Drug-induced pancreatitis.
Drug Saf. Jun; 14 (6): 406-423.
27. Scarpelli DG (1989): Toxicology of the pancreas. Toxicol.Appl.
Pharmacol. Dec; 101 (3): 543-554.
28. Helin H, Mero M, Helin M and Markkula H (1981): Elastic
tissue injury in human acute pancreatitis. Pathol. Res. Pract.
Jul; 172 (1-2): 170-175.
29. Pettit FH, Harper RF, Vilaythong J, Chu T and Shive W
(2003): Reversal of statin toxicity to human lymphocytes in tissue
culture. Drug Metabol.Drug Interact. ;19 (3):151-160.
30. Palomaki A, Malminiemi K, Solakivi T and Malminiemi
O (1998): Ubiquinone supplementation during lovastatin
treatment: Effect on LDL oxidation ex vivo. J.Lipid Res.
Jul; 39 (7): 1430-1437.
13. Mortensen SA, Leth A, Agner E and Rohde M (1997):
Dose-related decrease of serum coenzyme Q10 during
treatment with HMG-CoA reductase inhibitors. Mol.Aspects
Med. ;18 Suppl: SI37-144.
14. Dollery C, Boobis A, Rawlins M, Thomas S and Wilkins
M (1999): Therapeutic drugs. 2nd ed. Churchill Livingstone:
Edinburgh. P.S37.
15. Shults CW and Schapira AH (2001): A cue to queue for CoQ?
Neurology Aug 14;57(3):375-376.
16. Bancroft JD and Gamble M (2002): Theory and practice
of histological techniques. 5th ed. Churchill Livingstone:
London. P. 139.
319
AiL-JaVlj A-C-j^Jl (JJ&JU (jxilLinl 1« unil ' " ' j >»«*-1 4_iJlill 4-C-j«a^^Uj (I&JXJUJI 12 ^ - ^ ^i^Ji {ji^-^^^y^
(j-a r t r t - a 1.44 d u j a c l
. J J J J J S J V I J ^ j j J a J ) jg><ilLl Ig I^T\4,I tllliwJ! jXwaaJJ aJ J3j #S.l<ui f_yAi\ LiajJ -*a-a 3 . 6 ^ J^-i 1 0 j ^ P O ' V r^**-^
^J-uiilt pLwijIj 4_jjxo3l <_JC j V l tjl fri-klj (JJLJLUXJI <jl£-u>l ^>J*Jj ajPkij\\
»nib d l j j a J j j - g l n j - L l j j V i h U " ^ 4 JuWll L)!itiJlj
111 fs j l \ l (_£JJ_UIA (_5-lc j ( 4_)JA^11 <_}C j V ) (J^>*J (^-2 4_jj-<ul ^"l\-»jS K-il) (JiaJ i-jjjfe joS (jjJ>7J& (jba ■Lx±j~a d l j g . h l j ^ J ! / ^ ^ ! !
JaJA-all J J A J I J A A J ^ J I 4_LO j ^ j - l l V I AjLuill ^ ^ i ^ - ^ J ^ J ( — ' ^ j - ^ eAjj^ll dlLluaJl < i l j S ^ j j [ j j L i i C j j i 2 k JaaLjJ jJia ^jja^ll
^j-lll jjlJj-aJt ( ^ SiA. <JJ! CII^>J*J]1 eiA <_ijl£j tA jjji»lt Lj!iLaJl J A » J ^^-3 \jjAJj^j"n<iSl c_aljj ojoiS CLitjakS ilijAakj oljilLj
LS^-J)^*- * j ^ ^ C5_^C' J ^ °
J ^ ^ " ^ (jJjl"l."ili«J»"ll ( j l ^iJ-i ( j - * ^ l i l u U j . 1 Oj^
><LujLaJI
rt-3^V^
r^*^
t5^1 ^ l - J - ^ a V ^ (j^liuola-aiuillj t l i a J j C .
*LJa\jc-\ (Jjisll jj-ullmlaAiuJl A ^ J Q J J S p j ^ j V I J»XAJ U j ^ i 1 isJ^£1JiJ L>"^!J^^' C > ° j ' j ^ ^ '
320