The role of carbonyl reductases in biotransformation of bupropion and 4-methylnitrozamino-1-(3-pyridyl)-1-butanone by human placenta

Abstract

s / Drug and Alcohol Dependence 156 (2015) e102–e182 e161 The role of carbonyl reductases in biotransformation of bupropion and 4-methylnitrozamino-1-(3-pyridyl)-1-butanone by human placenta Tatiana Nanovskaya1, Valentina M. Fokina1,2, X. Wang1, Cheryl Oncken3, Mahmoud S. Ahmed1, Gary Hankins1 1 OBG the reaction is catalyzed primarily by 11 hydroxisteroid dehydrogenase (11 -HSD) and aldoketoreductases. Maternal cigarette smoking has been associated with prenatal exposure to NNK, which is the most abundant and potent carcinogen of cigarette smoke. One of the metabolic pathways of NNK is carbonyl reduction to 4-methylnitrosamino-1-(3-pyridyl)1-butanol (NNAL) that initiates NNK detoxification. The goal of the current investigation is to determine placental metabolism of NNK and to identify placental enzymes responsible for its reduction. Methods: Term placentas were collected from women who smoked during pregnancy and from non-smokers. NNK metabolism was determined in vitro using placental microsomal and cytosolic subcellular fractions; the formation of NNAL was quantified by HPLC-UV. Results: The apparent Km and Vmax values for the reaction in placental subcellular fractions were determined. The formation of NNAL in placentas of heavy smokers was lower than in placentas of non-smokers: 12.1±3.5 vs. 17±6.3nmolmgP−1 for cytosolic fraction (p methamphetamine>4-MePPP>4-MEC. Conclusions: The current findings demonstrated that three second-generation synthetic cathinones functioned as reinforcers in rats, providing some justification for permanent scheduling of these drugs by regulatory agencies. Future research in our laboratory will assess the reinforcing effectiveness of these three compounds with a behavioral economics approach. Financial support: This research was supported by the UMMC Drug Abuse Development Fund and R01 DA12970 to BB. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.439 Serotonin 5-HT2C receptors in the ventral subiculum regulate cocaine-evoked hyperactivity in rats Harshini Neelakantan1, Sonja J. Stutz1, Marcy J. Bubar1, Robert M. Sears3, Ralph J. DiLeone3, Kathryn A. Cunningham1,2 1 Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States 2 Department of Pharmacy, University of Texas Medical Branch, Galveston, TX, United States 3 Department of Psychiatry, Yale University, New Haven, CT, United States Aims: The ventral subiculum (vSUB) interconnects with limbiccorticostriatal circuit which regulates the behavioral effects of cocaine. Serotonin neurons innervate the vSUB, however, little is known about its role or the 5-HT receptors that are functionally relevant in this region. We investigated the vSUB localization of the 5-HT2C receptor (5-HT2CR) and its role in the control of cocaineevoked hyperactivity. Methods: The expression of the 5-HT2CR and co-localization with GAD 67 (marker for GABA) in the vSUB were evaluated using immunohistochemical analyses in rats (n=3).We employed virally mediated genetic knockdown strategy to test the hypothesis that knockdown of the 5-HT2CR in the vSUB of rats (n=5) will modulate cocaine-evoked hyperactivity. Motor activity was assessed after saline or cocaine (10–20mg/kg) in modified open-field chambers and analyzed using repeated measures two-way ANOVA. Results:Dense immunoreactivity (IR) for 5-HT2CRwasobserved throughout the vSUB. Only a small proportion of 5-HT2CR-IR was co-localized with GAD 67-IR that was restricted to the distal end