N‐oxidation of a tertiary amine (N,N‐dimethylaniline) by human fetal liver microsomes

Abstract

Many nitrogen-containing drugs and foreign compounds are N-oxygenated in vertebrates,20 including man. 4 . 7, 11, 12, 18,23,36 For certain drugs, N-oxygenation is a quantitatively important route of metabolism, at least in vitro. 3 , 6 Drug oxidations, including C-hydroxylations and N-dealkylations, are known to be catalyzed by liver microsomal enzymes and to be dependent on oxygen and reduced nicotinamide adenine dinucleotide phosphate (NADPH) for activity, and this is also true for N-oxygenation reactions. 2 , 37 However, while the classical drug-oxidative reactions and the N-oxygenation of primary amines are dependent on the NADPH-

Developmental Aspects of the Hepatic Cytochrome P450 Monooxygenase System

“…Indeed, Rane & Gustafsson (122) have provided indirect evidence for the production of epoxides in fetal liver by documenting the formation of a 16,17 -transglycolic metabolite from 4,16-andros tadien-3-one. Similar preparations also catalyze the generation of potentially toxic N-oxides from N,N-dimethylaniline through a process presumably independent of cytochrome P450 (133).…”

Structural and Catalytic Properties of the Mammalian Flavin-Containing Monooxygenase

“…FM03 appears to be the dominant form of FMO present in adult human liver microsomes, and FM02 and FM04, if present, are expressed at very low levels (128). AUV-Dimethylaniline TV-oxygenase activity has been observed in the presence of fetal human liver (129) and adult human renal microsomes (97), and it is likely FMOl is largely responsible for the fetal liver and adult renal FMO activity observed. However, other forms of FMO are undoubtedly also present and active in adult human kidney.…”

Sulphate and Glucuronic Acid Conjugation of Harmol in Human Fetal and Adult Liver Tissue

“…The human adult liver specimens were obtained within 20 min after life-supporting treatment was stopped. Isolation of liver microsomes and the 105,000 g supernatant fraction was carried out as previously described for fetal [Rane, 1974] and adult hepatic tissue [von Bahr et al, 1980] Harmol was incubated with either microsomes and uridine diphosphate glucuronic acid (UDPGA, 2.5 mM) or 105,000 g supernatant fraction. The latter was preincubated with 3 mM ATP and 10 mM MgP04 for 30 min, which was found to be optimal for the generation of 3-phosphoadenosine-5-phosphosulfate (PAPS).…”