Hepatotoxic and hepatoprotective potential of histamine (H2)-receptor antagonists

It has been increasingly recognized that the histamine (H2)-receptor antagonists are associated in rare instances with idiosyncratic hepatotoxic reactions and with drug interactions related to their inhibition of the hepatic cytochrome P-450 enzymes. What have not been appreciated until recently are the potential therapeutic benefits that may be derived from cytochrome P-450 inhibition. Evidence is presented here that cytochrome P-450 inhibition may protect against hepatic damage induced by acetaminophen and other drugs metabolized via this system. Acetaminophen hepatotoxicity is an especially important problem because of the widespread use of this agent and the evidence that the potential for such injury may be increased in alcoholic persons. Cimetidine has been used in selected cases, one of which is described here, to treat acetaminophen hepatotoxicity. All H2-receptor antagonists may not be alike in this regard. Experimental studies in animal models indicate that although cimetidine protects against the hepatotoxic effects of acetaminophen, ranitidine may actually potentiate hepatic damage. It is thought that the difference between these two H2-receptor antagonists may lie in their affinities for binding to the cytochrome P-450 enzymes. Cimetidine, which binds more strongly, inhibits this system more efficiently, whereas the inhibition produced by ranitidine is not sufficient to confer a protective effect against drug-induced hepatotoxicity.