Haematological, hepatic and renal alterations after repeated oral or intraperitoneal administration of monoisoamyl DMSA. I. Changes in male rats

Abstract

Monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), a vicinal thiol chelator, is gaining recognition recently as a better chelator than meso 2,3-dimercaptosuccinic acid (DMSA) in decreasing heavy metal burden in tissues because of its lipophilic character. There is, however, little information available on the toxicological properties of this chelator after repeated administration in animals. In the present study, we investigated the dose-dependent effect of MiADMSA on various biochemical parameters suggestive of alterations in haem biosynthesis and hepatic, renal and brain oxidative stress after 21 days of repeated intraperitoneal (i.p.) or oral (p.o.) administration to rats. The concentration of essential metals in blood and soft tissues was determined along with histopathological observations of hepatic and renal tissues. The results suggest that MiADMSA administration had no effect on blood delta-aminolevulinic acid dehydratase activity. However, an increase in zinc protoporphyrin and a decrease in haemoglobin levels were noted in animals given MiADMSA i.p. A moderate increase in serum alkaline phosphatase suggested mild hepatotoxicity at the highest dose (100 mg kg(-1), i.p.). This was confirmed by histopathological examinations, which identified basophilic stippling, granulation of the cytoplasm, haemorrhage and congestion. At the highest dose, levels of hepatic thiobarbituric acid reactive substance and oxidized glutathione were increased above those of control values. Levels of hepatic reduced glutathione were decreased. Taken together, these observations point to oxidative stress. In animals administered MiADMSA i.p. there was an increase in the brain malondialdehyde levels at the two higher doses (50 and 100 mg kg(-1)). Essential metal status revealed a significant effect of MiADMSA (p.o.) in increasing blood zinc while significantly decreasing the kidney zinc level. The most significant adverse effect of MiADMSA was on copper concentration, which showed significant depletion from almost all major organs. Magnesium levels in blood decreased but increased in liver of MiADMSA-administered rats. Histopathological observations of liver and kidneys suggest few moderate lesions. It can be concluded that repeated administration of MiADMSA is compromised with some mild toxic effect, particularly the loss of copper. The effects during oral administration are comparatively less pronounced than by the i.p. route.

Effects of lead on Epidermal wound Contraction and serum biochemistry in West African dwarf goats

“…This may be due to thrombocytopenia and thrombocytosis after chronic lead intoxication (Sudakova et al, 1983;Mugahi et al, 2003;Abdulkareem, 2010); while the insignificant increase in the white blood cell may be due to lead induced inflammation (Yagminas et al, 1990, Alwaleedi, 2015.Significant increase in ALT and AST which are biomarkers for liver toxicity was observed in this study (P<0.05), might be due to increased cell membrane permeability, increased cellular basal metabolic rate or cell membrane damage of hepatocytes caused by lead acetate. These results agree with previous studies reported an elevation in AST and ALT levels after treatment with lead due to acute hepatitis, jaundice, and liver cirrhosis in mice, human and rat (Mehta et al, 2002;Patil et al, 2007;Shalan et al, 2005, Alwaleedi, 2015, also in sheep (Badiei et al, 2009). The significant decrease in albumin at the reparatory phase E3 J. Med.…”

Strategies for Safe and Effective Therapeutic Measures for Chronic Arsenic and Lead Poisoning

“…Taubeneck et al showed that the developmental toxicity of DMSA is mediated mainly through disturbed copper metabolism and this may also be true for MiADMSA 72) . Recently, our group was the first to report the toxicological data on MiADMSA when administered in male and female rats 73,74) through the oral as well as the intraperitoneal route (25, 50 and 100 mg/kg/3 wk). We observed that there was no major alteration in the heme biosynthesis pathway except for a slight rise in the zinc protoporphyrin levels, suggesting mild anemia at the highest dose.…”

“…MiADMSA was seen to be slightly more toxic in terms of copper loss and some biochemical variables in the hepatic tissue of females as compared to male rats. The studies concluded that the administration of MiADMSA to female rats is confounded with side effects and may require caution during its use 73,74) . Since administration of chelating agents during pregnancy always requires caution, we studied the effects of MiADMSA administration from day 14 of gestation to day 21 of lactation at different doses through oral and ip routes to examine the maternal and developmental toxicity in the pups 75) .…”

Haematological, hepatic and renal alterations after repeated oral and intraperitoneal administration of monoisoamyl DMSA. II. Changes in female rats

“…or p.o. 5 days a week for 3 weeks (Mehta et al, 2002). The MiADMSA was dissolved in sodium bicarbonate solution and the solutions were prepared immediately before use.…”

“…or oral (p.o.) administration in male rats and observed that the higher doses could lead to moderate hepatotoxicity, signs of oxidative stress and significant loss of copper (Mehta et al, 2002). It is well known that the toxicity of chemicals may vary according to gender, thus we planned to study the effects of MiADMSA on parameters indicative of changes in haem biosynthesis, liver and kidney tissues and the concentration of essential metal in blood and soft tissues of female rats.…”