Identification of enzymes responsible for nitrazepam metabolism and toxicity in human.

摘要: Nitrazepam (NZP) is a hypnotic agent that rarely causes liver injuries in humans and teratogenicity rodents. In humans, NZP primarily metabolized to 7-aminonitrazepam (ANZP) by reduction subsequently 7-acetylamino nitrazepam (AANZP) acetylation. ANZP can be regenerated from AANZP hydrolysis rodents, but it still unclear whether this reaction occurs humans. may associated with teratogenicity, while known drug-induced caused reactive metabolite(s). study, we attempted identify the enzymes responsible for metabolism obtain basic understanding of process metabolite toxicities. We found reductase activity human cytosol (HLC) was higher than microsomes (HLM). purified enzyme(s) HLC aldehyde oxidase 1 (AOX1). The role AOX1 confirmed an observed increase upon addition N1-methylnicotinamide, electron donor AOX1, as well inhibition presence inhibitors. acetylated form N-acetyltransferase (NAT) 2. An experiment using recombinant esterases study HLM revealed hydrolyzed arylacetamide deacetylase (AADAC) liver. N-Hydroxylamino NZP, which suspected metabolite, detected conjugate N-acetyl-l-cysteine through hydroxylation reactions. latter reaction, readily formed CYP3A4 among various P450 isoforms tested. sum, NAT2, AADAC, are determinants pharmacokinetics they confer interindividual variability sensitivity side effects.