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BIFENDATE INDIRECTLY INHIBITS ALANINE TRANSAMINASE RELEASE WITHOUT DIRECT INTERACTION IN VITRO AND IN VIVO

Bifendate (DDB) is an approved hepatoprotective drug for decreasing serum transaminases in patients with chronic hepatitis in China. However, in some clinical reports, the level of alanine transaminase (ALT) could be rebounded after DDB treatment withdrawal and decreased again once re-treated with DDB, suggesting that DDB might be a reversible inhibitor of ALT or directly inhibit its activity or synthesis. To investigate whether DDB and its metabolites decrease transaminase levels by directly acting on transaminases or how DDB influences the liver transaminases, the dynamics of transaminase activity and protein level were detected after treatment with DDB or with its metabolites in vitro or in vivo. The results showed that DDB reduced the activities and the protein levels of serum ALT and aspartate transaminase in CCl4-induced mice without a significant effect on those in the liver. DDB and its metabolites did not affect the activity elimination rate and the protein degradation rate of ALT, while it significantly reduced the release of transaminases from the damaged primary mouse hepatocytes induced by CCl4. Therefore, DDB does not directly act on transaminases but indirectly decreases transaminase release in vitro and in vivo. Mechanism disclosure of DDB in our study contributes to its security evaluation, clinical practice, and the development of effective drugs derived from DDB.