Metabolism of the liver carcinogen N-nitrosopyrrolidine by rat liver microsomes.

Abstract

This report represents a study of the total metabolism of the hepatocellular carcinogen, N-nitrosopyrrolidine (NO-PYR), by rat liver microsomes and postmicrosomal supernatant. [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 nonmethylene chloride-extractable products follows simple Michaelis-Menten kinetics with an apparent Km of 3.6 x 10(-4) M NO-PYR. The major products of NO-PYR metabolism by rat liver microsomes and postmicrosomal supernatant have been 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 have also been found.