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Zaltoprofen Induces Histological Changes in Albino Rat Liver

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Zaltoprofen Induces Histological Changes in Albino Rat Liver ORIGINAL ARTICLE Eur. J. Anat. 17 (2): 123 –126 (2013) Zaltoprofen induces histological changes in albino rat liver Ramanathan Shalini*, Salem S. Rajasekar and Kazhumaram V.P. Suriyakumari Department of Anatomy, Sri Manakula Vinayagar Medical College and Hospital, Kalitheerthalkuppam, Madagadipet, Puducherry, India SUMMARY the levels of serum alanine transaminase at the Hepatic injury associated with nonsteroidal anti- end of 14 and 21 days. Zaltoprofen should be inflammatory drugs (NSAIDs) was found to be used cautiously in patients with liver diseases. variable ranging from mild cholestasis to severe hepatocellular injury. Zaltoprofen is a NSAID Key words: NSAIDs – Zaltoprofen – Liver histol- used commonly as an analgesic in the treatment ogy – Necrosis – Central vein of painful disorders. The aim of this study was to determine the histological changes in the liver of albino rats after varying periods of oral zalto- INTRODUCTION profen administration. Thirty-six adult male albino Wistar rats and the drug zaltoprofen at a dose of Nonsteroidal anti-inflammatory drugs (NSAIDs) 40 mg/kg were employed, and 10% dimethyl reduce pain in patients with painful disorders like sulphoxide was used as the solvent for the drug. Rheumatoid arthritis and osteoarthrirtis. Ehrlich Groups A1, B1 and C1 - each comprising 6 rats (2004) has reported that these agents also have served as control groups and were treated with unwanted effects on the gastrointestinal tract, 10% dimethyl sulphoxide, orally via an oro-gastric liver and kidneys. Scarpingnato and Hunt (2010) tube, for 7, 14 and 21 days respectively. Groups have reported that the gastrointestinal side ef- A2, B2 and C2 - each comprising 6 rats served fects of NSAIDS are ulceration, bleeding and per- as experimental groups and were treated with the foration of the stomach, as well as the small and drug zaltoprofen dissolved in 10% dimethyl sulph- large intestine. oxide orally via an oro-gastric tube, for 7, 14 and 21 days respectively. Blood samples were col- Aithal and Day (2007) reported that NSAIDs are lected from the tail vein of rats for analysis of se- among the most common drugs associated with rum alanine transaminase and serum aspartate drug-induced liver injury with an estimated inci- transaminase before the sacrifice. The rats were dence between 3 and 23 per 100,000 patient sacrificed 24 hours after the last dose of drug and years. Lewis et al. (1998) reported that the hepat- their liver was collected. The histological changes ic injury associated with NSAIDs was found to be noted at the end of 7 days of zaltoprofen admin- variable ranging from mild cholestasis to severe istration were central vein dilatation and conges- hepatocellular injury. NSAIDs like Rofecoxib and tion, periportal lymphocytic infiltration, and necro- Valdecoxib were also associated with hepatotoxi- sis in the peripheral region. After 14 days of drug city (Yan et al., 2006; Niranjan et al., 2010). administration, there was extensive necrosis up Zaltoprofen, chemically 2-(10,11-dihydro-10- to the central region. At the end of 21 days of oxodibenzo[b,f]thiepin-2-yl)propionic acid (Nirogi drug administration, there was dilation of bile et al., 2006) is a potent NSAID with preferential ducts as well. There was a significant increase in Cycloxygenase-2 inhibition (Hirate et al., 2006). It is used in the treatment of rheumatoid arthritis (Hatori and Kokubun, 1998), osteoarthritis * Corresponding author: R. Shalini. Department of Anatomy, (Pareek et al., 2011), as well as to relieve pain Sri Manakula Vinayagar Medical College and Hospital, Kali- theerthalkuppam, Madagadipet, Puducherry- 605107, India. Tel: 00 91 9841657895. E-mail: [email protected] Submitted: November 2, 2012 Accepted: March 14, 2013 123 Hepatic effects of Zaltoprofen after surgery, injury and tooth extraction 10% formalin, processed and stained with eosin (Muratani et al., 2005; Komiya et al., 2009). After and hematoxylin stains. oral administration of zaltoprofen to humans, 62% The experimental protocol was approved by the of the dose is excreted as conjugates in the urine Institutional Animal Ethics Committee following and only 3% is excreted unchanged (Furuta et the guidelines of CPCSEA (Committee for the al., 2002). Also the involvement of liver micro- Purpose of Control and Supervision of Experi- some CYP2C9 and UGT2B7 in the metabolism of ments on Animals for laboratory animal facility). zaltoprofen is established (Furuta et al., 2002). The aim of the study was to observe the histo- Statistical analyses logic changes in liver of albino rats treated with varying periods of zaltoprofen. The program Epi info version 3.4.3 was used in the statistical evaluation of the biochemical re- sults. Mean and standard deviation was calculat- MATERIALS AND METHODS ed for each of the groups. ‘F’ test was used to determine the ‘p’ value for each of the parame- Design ters. A ‘p’ value < 0.05 was taken to be statisti- cally significant. Thirty-six adult male albino Wistar rats, weigh- ing 180-220 g were obtained from animal house of Sri Manakula Vinayagar Medical College and Hospital, Puducherry, India. The rats were accli- RESULTS matized for a period of 7 days before starting the study. Standard environmental conditions such On histological examination, the liver of the as temperature (24 ± 2ºC), humidity (60-70%) control groups were normal (Fig. 1A and Fig. 1B). and 12 hours of light/dark cycle were maintained. The liver of the rats treated with the drug zalto- Food and water were allowed ad libitum under profen for 7 days (A2 group) showed histological strict hygienic conditions. changes. There was central vein dilatation and congestion (Fig. 1C), periportal lymphocytic infil- Rats were divided into six groups. Groups A1, tration (Fig. 1C) and coagulative necrosis of B1 and C1, each comprising 6 rats, served as the hepatocytes in the peripheral region (Fig. 1D). control groups and were treated with isovolumet- On biochemical evaluation serum aspartate ric quantities of 10% dimethyl sulphoxide, orally transaminase levels were significantly increased via an oro-gastric tube, for 7, 14 and 21 days re- with a ‘p’ value of 0.04 (Table 1). spectively. Groups A2, B2 and C2, each compris- ing 6 rats, served as the experimental group and The histological changes observed in the liver were treated with the drug zaltoprofen (Ipca La- of the rats treated with the drug Zaltoprofen for boratories Ltd) in a dose of 40 mg/kg body 14 days (B2 group) were central vein dilatation weight/day (Kiso to Rinsho, 1990) dissolved in and congestion, periportal lymphocytic infiltration 10% dimethyl sulphoxide, orally via an oro-gastric (Fig. 2A), and extensive coagulative necrosis of tube, for 7, 14 and 21 days respectively. hepatocytes extending upto the central region (Fig. 2B). On biochemical evaluation serum ala- Blood samples were collected from the tail vein nine transaminase levels were significantly in- of the rats, before they were sacrificed, for bio- creased with a ‘p’ value of 0.03 (Table 1). chemical analysis of serum alanine transaminase (ALT) and serum aspartate transaminase (AST). The histological changes observed in the liver The rats were sacrificed 24 hours after the last of the rats treated with the drug Zaltoprofen for dose of the drug by cervical dislocation and their 21 days (C2 group) were central vein dilatation liver was collected. The organs were preserved in and congestion (Fig. 2C), periportal lymphocytic infiltration, dilatation of bile ducts (Fig. 2D) and Table 1. Biochemical parameters Group A1 Group A2 Group B1 Group B2 Group C1 Group C2 ‘p’ value ‘p’ value ‘p’ value n= 6 n= 6 n= 6 n= 6 n= 6 n= 6 Serum alanine transaminase 33.67 ± 36.5 ± 41.5 ± 53.17 ± 42.5 ± 54.33 ± (ALT) U/lt Mean 0.558 0.034 0.030 7.81 8.53 7.69 9.49 4.67 5.85 ± SD Serum aspartate transaminase 169.17 229 ± 171.33 194.33 147 ± 157 ± (AST) U/lt 0.040 0.071 0.720 ± 50.4 40.68 ± 26.34 ± 11.97 53.31 40.58 Mean±SD 124 R. Shalini et al. Fig. 2. (A) Liver of B2 group rat. The thin arrow points Fig. 1. (A) Liver of control group rat (x10). (B) Liver of to periportal lymphocytic infiltration (x40). (B) Liver of control group rat (x40). (C) Liver of A2 group rat. B2 group rat. This slide indicates extensive necrosis of The thick arrow represents dilated and congested hepatocytes (x40). (C) Liver of C2 group rat. The thick central vein and the thin arrow points to lymphocytic arrow indicates dilated and congested central vein and infiltration (x10). (D) Liver of A2 group rat. The thick thin arrow indicates necrotic hepatocytes near the cen- arrow indicates necrotic hepatocytes and the thin arrow tral vein (x10). (D) Liver of C2 group rat. The thick ar- indicates normal hepatocytes (x10). row points to dilated bile duct (x40). extensive coagulative necrosis of hepatocytes up toxic effects of indomethacin, piroxicam, aspirin to the central region (Fig. 2C). On biochemical and phenylbutazone in the liver of albino rats. evaluation serum alanine transaminase levels They observed increased levels of serum aspar- were significantly increased with a ‘p’ value of tate transaminase and periportal hepatic necrosis 0.03 (Table 1). and kuppfer cell proliferation in the indomethacin treated group. DISCUSSION Hummdi and Habashi (2010) have reported that Hepatic dysfunction has been associated with lornoxicam caused-hepatocyte hypertrophy with the clinical use of NSAIDS. The present study of pyknosis of nuclei, blood sinusoidal collapse and the use of varying periods of zaltoprofen admin- cellular infiltration. istration to Albino rats showed that there was a Somchit et al. (2004), from Malaysia, observed borderline increase in the level of liver enzymes the histological changes in liver of mice after ad- and the histological changes observed were peri- ministration of mefenamic acid for 14 days.
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