Haematological, hepatic and renal alterations after repeated oral or intraperitoneal administration of monoisoamyl DMSA. I. Changes in male rats.
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.
Mehta
Ashish
A
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior-474002, India.
Kannan
G M
GM
Dube
S N
SN
Pant
B P
BP
Pant
S C
SC
Flora
S J S
SJ
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000008:administration & dosage / Q000633:toxicity*; D003300:Copper / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006418:Heme / Q000096:biosynthesis; D007274:Injections, Intraperitoneal; D007501:Iron / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D004113:Succimer / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D014018:Tissue Distribution; D015032:Zinc / Q000097:blood
D002614:Chelating Agents; D006418:Heme; D003300:Copper; C091888:monoisoamyl-2,3-dimercaptosuccinate; D004113:Succimer; D007501:Iron; D015032:Zinc