The effect of methoxsalen on nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in vivo.
Nicotine is metabolized to the inactive metabolite cotinine by cytochrome P450 2A6. NNK, or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is a potent procarcinogen shown to be activated to a reactive mutagenic metabolite by the enzyme CYP2A6. We studied the effect of inhibiting CYP2A6 on smoking behavior and metabolism of the procarcinogen NNK. In study 1, abstinent smokers (n=7) received methoxsalen (a potent CYP2A6 inhibitor), 30-50 mg orally, one-half hour before three subcutaneous nicotine injections (31 microg/kg) were given at hourly intervals. Methoxsalen increased mean plasma nicotine by 47% (p<.01) and mean nicotine area under the curve (AUC) by 63% (p<.0001); and decreased nicotine clearance by 39% (p<.0001), relative to placebo. In study 2, smokers (n=11) were told to maintain their same number of cigarettes smoked while receiving methoxsalen, 10 mg orally three times daily for 3 days. On day 3 of methoxsalen treatment, a 29% increase in plasma nicotine/expired-air CO (an index of smoke exposure) (p=0.03) was observed. Urinary levels of trans 3'-hydroxycotinine (metabolized by CYP2A6 from cotinine) also were decreased (p<.0001), and significantly more NNK was metabolized to the inactive NNAL-glucuronide (1.04+/-0.54 pmol/mg on day 1 to 1.37+/-0.74 pmol/mg on day 4, p<.01) relative to placebo. Thus, treatment with the CYP2A6 inhibitor methoxsalen in vivo increases the routing of NNK to the inactive NNAL-glucuronide and decreases smoking. CYP2A6 inhibition may have potential as an exposure reduction or cessation strategy in tobacco dependence.
Sellers
Edward M
EM
Department of Pharmacology, and Centre for Research in Women's Health, University of Toronto, Ontario, Canada. e.sellers@utoronto.ca
Ramamoorthy
Yamini
Y
Zeman
Marilyn V
MV
Djordjevic
Mirjana V
MV
Tyndale
Rachel F
RF
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism*; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D005731:Ganglionic Stimulants / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000494:pharmacology; D009538:Nicotine / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D009602:Nitrosamines / Q000378:metabolism*; D010919:Placebos; D012907:Smoking
D002273:Carcinogens; D005731:Ganglionic Stimulants; D009602:Nitrosamines; D010919:Placebos; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D008730:Methoxsalen