Evidence for the possible formation of a toxic tyrosine metabolite by the liver microsomal drug metabolizing system.

The toxicity of tyrosine in the mouse was found to be affected by agents which interact with the liver microsomal drug metabolizing system. Pretreatment of mice with SKF 525A or cobaltous chloride, two different types of inhibitors of the drug metabolizing system, afforded a marked protection against tyrosine toxicity. Pretreatment with phenobarbital or 3-methylcholanthrene, two inducers of the drug metabolizing system, potentiated the toxic effects of tyrosine. Toxicity, as determined by lethality, was also found to be correlated with a depletion of liver glutathione levels. It is concluded that the liver microsomal drug metabolizing system is capable of converting tyrosine to a toxic metabolite, conceivably a 2.3 epoxide of tyrosine. The present results are discussed in relation to the human disease tyrosinemia (tyrosinosis).