Printed in L’.S.A. PROPERTIES OF MICROSOMAL ENZYME SYSTEMS THAT REDUCE N-HYDROXYPHENTERMINE

The reduction of N-hydroxyphentermine was studied in liver microsomes isolated from rat. guinea pig, and rabbit. The reduction requires a NADPH-generating system and was inhibited by oxygen and carbon monoxide. In the rat, the reduction was increased by phenobarbital pretreatment. Kinetic analysis of the reductase activity in rat liver microsomes suggests that the reduction of the hydroxylamine is mediated by at least two enzyme systems. one of which is a CO-sensitive system inducible by phenobarbital. N-Hydroxylation is a major in vitro metabolic pathway of primary arylalkylamines in liver mi-crosomal preparations from several species includ-ing the rat, rabbit, and guinea pig (1-5). In whole-animal studies, Caldwell et a!. adminis-tered p-chlorophentermine orally to several species and identified the hydroxylamine as a metabolite in the urine of man, rhesus monkey, rabbit, and guinea pig but not in the urine of the rat and marmoset (6). The N-hydroxy metabolite of phentermine has also been reported in human urine (7). However, examination of the fate of systemically administered hyd roxylam i nes such as N-hydroxyindolealkylamines (8), N-hydroxy-phentermine (9), and N-hydroxy-p-chloroamphet-amine (10) in rats and mice indicate that they are rapidly reduced to the corresponding amine. It appears, therefore, that although most species are capable of forming hydroxylamines, some species appear to be able to reduce them more effectively than others. The existence of a NADPH-dependent aromatic nitro and hydroxylamine reductase in rat liver microsomes has been known for some time (II, 12). Ziegler and his co-workers have also described a NADH-dependent hydroxylamine reductase in porcine liver microsomes (13, 14) which has re-cently been purified and characterized. Thus, there This work was supported by United States Public Healt