Paper Information

Title: 

CONTRIBUTION OF INDUCIBLE FACTORS IN PROTECTION AGAINST DAMAGES INDUCED BY HEPATOTOXIC DRUGS IN IMMATURE RATS

Type: SPEECH
Author(s): ALAMEH A.*,ANSARI HADIPOUR H.,DADKHAH A.,KAZEMNEZHAD S.
 
 *DEPARTMENT OF BIOCHEMISTRY, FACULTY OF MEDICAL SCIENCES, TARBIAT MODARRES UNIVERSITY TEHRAN
 
Name of Seminar: IRANIAN CONGRESS OF TOXICOLOGY
Type of Seminar:  CONGRESS
Sponsor:  SOCIETY OF TOXICOLOGY
Date:  2004Volume 8
 
 
Abstract: 

Generally, it is accepted that immature animals are less resistant to toxic effects of drugs. The molecular basis of susceptibility to toxicant is probably due to deficiency in the one or more key factors involved in drug metabolism pathways. Drug metabolizing system is underdeveloped in developing rats; hence, they may by less resistant to toxic compounds at early stages of life. We have previously shown that phase I and II drug metabolism in liver tissue are much lower in newborn rats. The activities of cytochrome P-450, GSH S-transferase and cellular GSH content in liver of young rats found to be 30-40% of that measured in adults. This comparison is based on the data obtained from animals never exposed to a toxic compound. However, susceptibility/resistance can better be judged when animals are challenged with high dose toxin. In this presentation we report the response of two systems namely drug metabolizing system and antioxidant factors in young and adult rats challenged with different toxicants.
The rate of glutathione (GSH) conjugate formation to acetaminophen (APAP) in liver preparation was measured by HPLC. Comparison of the key factors involved in APAP detoxification revealed that certain factors are induced differentially in immature and adult rats in response to high dose drugs. Liver cytosolic GSH S-transferase activity was measured spectrophotometrically using CDNB as substrate. GSH S-transferase induction in young and adults was further verified using Western blotting as well as RT-PCR techniques. Depletion in liver GSH and the pattern of re-synthesis of GSH was estimated by measuring liver GSH in both the age groups under drug treatments. Parameters related to antioxidant system were also examined in rats challenged with high dose acetaminophen or menadione. Antioxidant enzymes such as catalase and superoxide dismutase (SOD) together with selected non-enzymatic assays such as bilirubin and GSH were compared in liver and plasma samples obtained from young and adult rats. Total antioxidant of plasma was measured using ferric reducing ability of plasma (FRAP assay). The influence of antioxidant factors on formation of lipid peroxidation products was examined by measuring thiobarbituric acid reacting substances (TBARS).
The rate of glutathione (GSH) conjugate formation to acetaminophen (APAP) in liver preparation in developing rats was ~24 fold greater than that measured in adults treated with a single high dose (500 mg/kg bw) of the drug. A surge in APAP-GSH conjugate formation in liver of young rats was associated with elevation in cytosolic GSH S-transferase in young rats. In case of antioxidant system, high dose APAP (450 mg/kg bw) caused a surge in FRAP. This finding was associated with increase in bilirubin as well as SOD. Increased FRAP was inversely related to the rate of TBARS in both plasma and liver.
These results suggest that induction in certain factors (mostly enzymes) in liver tissue and blood of developing animals play a major role in detoxification of toxicants. This system is induced in response to high dose toxins to compensate deficiencies in detoxification pathways in immature rats.

 
Keyword(s): 
 
Yearly Visit 5   tarjomyar
 
Latest on Blog
Enter SID Blog