METABOLISM OF THE LIVER CARCINOGEN N-NITROSOPYRROLIDINE BY RAT-LIVER MICROSOMES

Abstract

A study of the total metabolism of the hepatocellular carcinogen, N-nitrosopyrrolidine (NO-PYR), by rat liver microsomes and postmicrosomal supernatant was performed. [2,5-14C]NO-PYR, which is totally extractable from aqueous solution with methylene chloride, is converted to radioactive nonmethylene chloride-extractable products by these fractions. The initial rate of conversion to nomethylene chloride-extractable products follows simple Michaelis-Menten kinetics with an apparent Km of 3.6 .times. 10-4 M NO-PYR. The major products of NO-PYR metabolism by rat liver microsomes and postmicrosomal supernatant were isolated and identified. One product of metabolism of NO-PYR is 2-hydroxytetrahydrofuran formed by .alpha.-hydroxylation by the microsomes. In the presence of postmicrosomal supernatant enzymes, this compound exists only as a transient intermediate which is rapidly converted to 1,4-butanediol or .gamma.-hydroxybutyrate. These compounds may be cycled into general cellular metabolism resulting in the production of CO2. Two minor pathways of metabolism were also found.