Modulatory role of betulinic acid in N-nitrosodimethylamine-induced hepatorenal toxicity in male Wistar rats

Abstract

<jats:p> N-nitrosodimethylamine (NDMA) is a toxicant found in foods and drinking water. Several synthetic agents used in alleviation of NDMA toxicity have been associated with serious side effects. Therefore, a safe and less toxic agent is desirable. In this study, betulinic acid (BA), a triterpenoid antioxidant, is proposed as a better and alternative agent to modulate NDMA-induced toxicity. Twenty-four Wistar rats were assigned into four groups of six rats each and treated with normal saline (control), BA (25 mg/kg), NDMA (5 mg/kg) and (BA + NDMA). BA was given by oral gavage for 14 consecutive days, while NDMA was administered intraperitoneally on days 7 and 12. Results showed that administration of NDMA significantly ( p &lt; 0.05) elevated the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase and gamma-glutamyl transferase by 51%, 48% and 81%, respectively. Also, NDMA intoxication significantly ( p &lt; 0.05) increased the levels of serum urea and creatinine by 64% and 82%, respectively, and decreased urinary creatinine by 67%. In addition, administration of NDMA significantly ( p &lt; 0.05) increased the levels of hepatic and renal DNA fragmentation by 44% and 61%, respectively, relative to control. The number of micronucleated polychromatic erythrocytes (mnPCEs) in NDMA-treated rats (11.1 ± 2.6 mnPCE/1000PCE) was significantly higher than control (4.3 ± 1.1 mnPCE/1000 PCE). Immunohistochemistry revealed strong expressions of Bcl-2 and nuclear p53 in NDMA-intoxicated rats. Interestingly, pretreatment with BA significantly ( p &lt; 0.05) ameliorated NDMA-induced changes in serum biochemical indices, mnPCEs, DNA fragmentation and expressions of Bcl-2 and p53 proteins. These findings suggest that BA protects against NDMA-induced toxicity via anti-oxidative and anti-apoptotic activities. </jats:p>

Betulinic acid protects againstN-nitrosodimethylamine-induced redox imbalance in testes of rats

“…The combined depletion of GSH, reduction of GPx and GST activities strongly suggest that NDMA may adversely affect glutathione metabolic pathway and promote oxidative damage in the testes. The observed effect of NDMA on markers of oxidative stress is consistent with previous studies [6,7,41]. However, supplementation with BA improved the antioxidant status (enzymatic and non-enzymatic) of NDMA-treated animals.…”

“…The ability of BA to reduce the weight and relative weight of testes of NDMA-treated indicates that this triterpenoid could protect against NDMA-induced testicular hypertrophy. NDMA is a toxicant found in processed foods and ground water, and its adverse impacts on organs, especially liver and kidney, have been studied [7]. However, there is a dearth of information on the effect of this toxicant on male reproductive system.…”

“…The BA and NDMA were separately dissolved in normal saline. The choice of dosage and vehicle was based on a previous study [7]. BA was given by gavage for 14 consecutive days, while NDMA was given intraperitoneally on days 7 and 12 of the study.…”

“…It is also known that the carcinogenicity of nitrosamines is directly proportional to activities of the activating enzymes [5]. Recently, our studies on the hepatorenal toxicity of NDMA linked the toxicity of the toxicant to increase in DNA fragmentation, expression of Bcl-2, p53, Ki-67 and CD15 in rats [6,7]. However, there is a dearth of information on the effects of NDMA on male reproductive system.…”

Nephroprotective effect ofFerulago angulataflowers on N‐nitrosodimethylamine‐induced nephrotoxicity in rats and its phytochemical profile

“…It can generate harmful radicals in cellular systems. Nitrogen oxide which is produced during the N‐nitrosamine metabolism can cause the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Adeleke & Adaramoye, ).When the generation of RNS/ROS is greater than the capability of antioxidant defense systems, the balance between ROS and antioxidants is impaired, causing oxidative and nitrative damage to cellular components, such as proteins, DNA, and lipids, which is known as oxidative and nitrative stress (Chao, Hsu, Liu, Lin, & Hu, ).…”