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 mu mol/kg) s.c. dose of nicotine effected a transient, lung-specific induction of cytochrome P-4 50 (CYP) 1A1 in the rat, a dose-response study and assessment of the lung s pecificity of the induction was limited by toxicity of the acute parenteral nicotine exposure. In the present study, we examined the dose-CYP1A1/2 ind uction 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 liqu id 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 li ver 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, b ut 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, respective ly, in the lung, 1.4-, 1.7-, and 15.9-fold, respectively, in the kidney, an d 1.7-, 2.9-, and 5.1-fold, respectively, in the liver. Similarly, albeit t o lower extents, the dietary alkaloid induced the CYP1A2-preferential activ ity methoxyresorufin O-demethylase in all three tissues dose-dependently. P lasma 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.