ABSTRACT
BACKGROUND/AIMS: The aim of this study was to investigate the precise mechanism of liver failure by hydralazine derivatives, with special reference to liver regeneration failure. METHODS: Histone acetylation and proliferation of hepatocytes were evaluated by immunohistochemistry with anti-acetylated histone H4 and proliferating cell nuclear antigen (PCNA). Inhibition of histone acetylation by drugs was determined by in vitro histone acetylation assay. Mice livers fed with todralazine for 1 or 4 months were subjected to immunohistochemistry and Western blotting. Todralazine-fed mice were challenged with anti-Fas to check liver regeneration failure. RESULTS: On immunohistochemistry, histone acetylation in the hepatocytes was significantly impaired in patients with hydralazine derivatives. In an in vitro acetyl transferase assay, histone acetylation was inhibited by hydralazine derivatives in a dose-dependent manner. Mice fed with todralazine (3mg/day) for 4 months showed impairment of histone acetylation in hepatocytes whereas no inhibition was observed in mice fed with todralazine for 1 month. Anti-Fas challenge to todralazine-fed mice resulted in impairment of liver regeneration in respect of liver weight loss with impairment of histone acetylation in hepatocytes. CONCLUSIONS: Todralazine could inhibit catalysis of histone acetyltransferase and long-term administration of todralazine may impair histone acetylation of the hepatocytes, resulting in liver regeneration failure.
Subject(s)
Histones/antagonists & inhibitors , Hydralazine/analogs & derivatives , Liver Failure/chemically induced , Liver Failure/metabolism , Todralazine/toxicity , Acetylation/drug effects , Acetyltransferases/analysis , Animals , Arylamine N-Acetyltransferase/genetics , Disease Models, Animal , Female , Histones/metabolism , Humans , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Failure/pathology , Liver Regeneration/drug effects , Mice , fas Receptor/antagonists & inhibitorsSubject(s)
Antihypertensive Agents/toxicity , Histones/drug effects , Liver Failure/chemically induced , Liver/drug effects , Todralazine/toxicity , Acetylation/drug effects , Animals , Antihypertensive Agents/adverse effects , Histones/metabolism , Humans , Liver/metabolism , Liver Failure/metabolism , Mice , Todralazine/adverse effectsABSTRACT
The genotoxicity of antihypertensive drugs, hydralazine, dihydralazine and binazine was assessed on the base of their capacity to induce micronuclei in L929 cell line. In our previous investigations we indicated that these drugs did not induce micronuclei in bone marrow polichromatic erythrocytes in PZH SFISS mice. Present results show that hydralazine and dihydralizine can induce micronuclei in vitro and that this effect depends on time of exposure and the concentration of drug.
Subject(s)
Antihypertensive Agents/toxicity , Dihydralazine/toxicity , Hydralazine/toxicity , Todralazine/toxicity , Animals , Cell Line/drug effects , Mice , Micronucleus TestsABSTRACT
The mutagenic and genotoxic activities of binazine and hydralazine were studied. In the Ames test, both with and without S-9 fraction, hydralazine was mutagenic in strains Salmonella typhimurium TA100 and TA1537, whereas binazine was not mutagenic in these strains. Both drugs were negative in mice micronucleus test.
Subject(s)
Antihypertensive Agents/toxicity , Hydralazine/toxicity , Mutagens/toxicity , Todralazine/toxicity , Animals , Male , MiceABSTRACT
Acute intravenous toxicity and antihypertensive activity of KB1, a novel todralazine analog was investigated and compared with the effects of todralazine (Td) in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. LD50 values were 72 mg.kg-1 for KB1, and 255 mg.kg-1 for Td in WKY and 43 mg.kg-1 or KB1 in SHR. Therefore, the toxicity of KB1 was higher than that of Td and it increased in SHR. The antihypertensive activity of KB1 (ED20% 9.8 mg.kg-1) in WKY was about 9 times less potent in comparison with Td (ED20% 1.1 mg.kg-1). Blood pressure reducing activity of KB1 augmented apparently in SHR (ED20% 2.5 mg.kg-1) whereas Td had not such an effect (ED20% 1.0). Thus, the influence of Td on blood pressure was similar in normotensive and hypertensive animals. Our results indicate that KB1 is capable of reducing blood pressure preferentially in hypertension.
