Dose-dependent up-regulation of rat pulmonary, renal, and hepatic cytochrome P-450 (CYP) 1A expression by nicotine feeding.
In a previous study in which a single 2.5 mg/kg (15.4 micromol/kg) s. c. dose of nicotine effected a transient, lung-specific induction of cytochrome P-450 (CYP) 1A1 in the rat, a dose-response study and assessment of the lung specificity of the induction was limited by toxicity of the acute parenteral nicotine exposure. In the present study, we examined the dose-CYP1A1/2 induction response relationship and the tissue specificity of the induction by orally administered nicotine, which lacks the toxicity of the parenterally administered drug. Nicotine, administered in a nutritionally balanced liquid diet, at a level of 20 (low), 60 (medium), or 200 (high) mg/kg of diet, induced CYP1A1 in the lung and kidney in a dose-dependent manner and in the liver at the high nicotine dose only, whereas CYP1A2 was induced in the liver dose-dependently and in the kidney at the high nicotine dose only. The high nicotine dose up-regulated mRNA level in the three tissues examined, but with the lung being the most responsive to the up-regulation. Induction of the CYP1A1-preferential activity ethoxyresorufin O-deethylase by the low, medium, and high nicotine diets was 1.9-, 4.9-, and 21.6-fold, respectively, in the lung, 1.4-, 1.7-, and 15.9-fold, respectively, in the kidney, and 1.7-, 2.9-, and 5.1-fold, respectively, in the liver. Similarly, albeit to lower extents, the dietary alkaloid induced the CYP1A2-preferential activity methoxyresorufin O-demethylase in all three tissues dose-dependently. Plasma nicotine concentration correlated neither with the dietary nor intake dose of the alkaloid nor with tissue levels of CYP1A, especially with the high-dose diet. Plasma nicotine levels at which CYP1A induction was maximal were comparable to those reported in smokers, suggesting that nicotine may induce CYP1A1 in humans.
Iba
M M
MM
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA. iba@eohsi.rutgers.edu
Fung
J
J
Pak
Y W
YW
Thomas
P E
PE
Fisher
H
H
Sekowski
A
A
Halladay
A K
AK
Wagner
G C
GC
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D003367:Cotinine / Q000097:blood; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009538:Nicotine / Q000097:blood / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000097:blood / Q000494:pharmacology*; D010088:Oxidoreductases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020318:Rats, Long-Evans; D015854:Up-Regulation / Q000187:drug effects*
D018722:Nicotinic Agonists; D012333:RNA, Messenger; D009538:Nicotine; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019363:Cytochrome P-450 CYP1A1; D003367:Cotinine