Nicotine metabolism in pregnant and nonpregnant rabbits

Smoking during pregnancy remains a major public health concern and is associated with numerous adverse effects. Recently the clearance of nicotine and cotinine was shown to be substantially increased in pregnant women compared with nonpregnant controls. The present study investigated the usefulness of the rabbit for studying the molecular basis for the observed changes in nicotine and cotinine disposition during pregnancy. Nicotine was largely metabolized to cotinine in rabbit liver microsomes (approximately 50% of total metabolism); significant amounts of nicotine-N'-oxide and nornicotine also were detected. The conversion of nicotine to cotinine also was detected in rabbit placental and fetal liver microsomes, albeit at only a fraction of the rate found in adult rabbit liver microsomes. The major products of cotinine metabolism in rabbit liver microsomes were 5'-hydroxycotinine, cotinine-N'-oxide, and norcotinine. Differences between human and rabbit liver were most apparent for cotinine. The major human metabolite, 3'-hydroxycotinine, was formed at only low levels in rabbit liver microsomes. Pregnancy had no effect on the metabolism of nicotine or on the expression of CYP2A6 immunoreactive proteins in rabbit liver microsomes. These studies provide a complete quantitative assessment of nicotine metabolism in rabbit liver microsomes and suggest that the rabbit may not be an appropriate animal model to study the effects of pregnancy on nicotine and cotinine metabolism. However, a molecular understanding of these effects is essential for prediction of the pharmacological and toxicological consequences of smoking during pregnancy.