Lung prostaglandin H synthase and mixed-function oxidase metabolism of nicotine.
Nicotine, a major constituent of cigarette smoke, was metabolized by lung microsomes to an aqueous soluble metabolite after addition of arachidonic acid. Similar results were observed with ram seminal vesicle microsomes. Metabolism was inhibited by indomethacin, propylthiouracil and methimazole but not glutathione. Data are consistent with metabolism being catalyzed by the hydroperoxidase activity of prostaglandin H synthase. The product was identified by mass spectrometry as 3-(2,3-dihydro-1-methyl-2-pyrrolyl)pyridine. Addition of NADPH resulted in formation of a different aqueous soluble product and also an organic extractable product. NADPH-dependent products were inhibited by 2-[(2,4-dichloro-6-phenyl)phenoxy]ethylamine, suggesting mixed-function oxidase catalyzed metabolism. The organic soluble product was identified as cotinine. Cotinine formation was inhibited by glutathione. 3-(2,3-dihydro-1-methyl-2-pyrrolyl)Pyridine was identified in urine from rabbits administered nicotine and from a male cigarette smoker. The amount of peroxidatic product in urine from rabbit and humans was 15 and 6%, respectively, that observed for cotinine. Thus, peroxidation represents a new metabolic pathway for nicotine which involves the peroxidatic activity of prostaglandin H synthase.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008861:Microsomes / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000502:physiology*; D009249:NADP / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism; D009538:Nicotine / Q000378:metabolism*; D010545:Peroxides / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011817:Rabbits
D001095:Arachidonic Acids; D010545:Peroxides; D016718:Arachidonic Acid; D009249:NADP; D009538:Nicotine; D006899:Mixed Function Oxygenases; D011451:Prostaglandin-Endoperoxide Synthases