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Abstract: Drosophila big brain (bib) encodes for a protein similar to members of the major intrinsic protein family, which includes the water- and ion-conducting aquaporin (AQP) channels. In mammals, AQP dysregulation has been implicated in a variety of diseases, including colorectal cancer and colonic injury. However, the regulatory mechanisms of AQP expression remain to be clearly elucidated. In this study, as we found a DREF binding site (DRE) in the 5′-flanking regions of both the Drosophila bib gene and the human AQP1 gene, we assessed the role of DREF in bib gene expression. DREF in Drosophila and humans has been demonstrated to function as a key transcriptional activator for cell proliferation-related genes. Herein, we demonstrate that the DRE is required for optimal promoter activity of Drosophila bib gene, particularly in the larval imaginal discs, which are actively proliferating tissues, as well as the adult hindgut. Our results may provide insight into the mechanisms inherent to the regulation of mammalian AQP genes. [Copyright &y& Elsevier]

Nicotine is an alkaloid found in tobacco. Human exposure to nicotine primarily occurs through the use of tobacco products. To date, limited nicotine pharmacokinetic data in animals have been reported. This study exposed male Sprague-Dawley rats to vehicle (and/or air) or four doses of nicotine via nose-only inhalation (INH), oral gavage (PO), and intravenous (IV) infusion. Plasma, six tissues (brain, heart, lung, liver, kidney, and muscle), and urine were collected at multiple timepoints from 5 minutes to 48 hours post-dose. The concentrations of nicotine, cotinine, and trans-3'-hydroxycotinine (3-OH-cotinine) were determined, and the pharmacokinetic profiles were compared among the four doses for each route. The results indicated that after single nicotine dose, nicotine bioavailability was 53% via PO. Across all the administration routes and doses, nicotine was quickly distributed to all six tissues; kidney had the highest nicotine and cotinine levels, and the lung had the highest 3-OH-cotinine levels; nicotine was metabolized extensively to cotinine and cotinine was metabolized to a lesser extent to 3-OH-cotinine; the elimination of plasma nicotine, cotinine, and 3-OH-cotinine followed first-order kinetics; plasma nicotine had a shorter half-life than cotinine or 3-OH-cotinine; the half-lives of plasma nicotine, cotinine, and 3-OH-cotinine were dose- and route-independent; and nicotine and cotinine were major urinary excretions followed by 3-OH-cotinine. Nicotine, cotinine, and 3-OH-cotinine levels in plasma, tissues, and urine exhibited dose-dependent increases. These study findings improve our understanding of the pharmacokinetics of nicotine, cotinine, and 3-OH-cotinine across different routes of exposure., (Published by Oxford University Press 2024.)

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a genotoxic carcinogen found in tobacco and tobacco smoke. Several in vitro and in vivo assays have been used for evaluating the genotoxicity of tobacco smoke and tobacco smoke constituents like NNK, yet it is not clear which in vitro assays are most appropriate for extrapolating the in vitro responses of these test agents to animal models and humans. The Pig-a gene mutation assay can be performed in vitro, in laboratory animals, and in humans, a potential benefit in estimating in vivo responses from in vitro data. In the current study we used Pig-a as a reporter of gene mutation both in vitro, in L5178Y/Tk +/- cells, and in vivo, in Sprague-Dawley rats. NNK significantly increased Pig-a mutant frequency in L5178Y/Tk +/- cells, but only at concentrations of 100 μg/ml and greater, and only in the presence of S9 activation. Pig-a mutations in L5178Y/Tk +/- cells were detected in 80% of the NNK-induced mutants, with the predominate mutation being G→A transition; vehicle control mutants contained deletions. In the in vivo study, rats were exposed to NNK daily for 90 days by inhalation, a common route of exposure to NNK for humans. Although elevated mutant frequencies were detected, these responses were not clearly associated with NNK exposure, so that overall, the in vivo Pig-a assays were negative. Thus, while NNK induces mutations in the in vitro Pig-a assay, the in vivo Pig-a assay has limited ability to detect NNK mutagenicity under conditions relevant to NNK exposure in smokers., (Published by Elsevier B.V.)

Drosophila big brain (bib) encodes for a protein similar to members of the major intrinsic protein family, which includes the water- and ion-conducting aquaporin (AQP) channels. In mammals, AQP dysregulation has been implicated in a variety of diseases, including colorectal cancer and colonic injury. However, the regulatory mechanisms of AQP expression remain to be clearly elucidated. In this study, as we found a DREF binding site (DRE) in the 5'-flanking regions of both the Drosophila bib gene and the human AQP1 gene, we assessed the role of DREF in bib gene expression. DREF in Drosophila and humans has been demonstrated to function as a key transcriptional activator for cell proliferation-related genes. Herein, we demonstrate that the DRE is required for optimal promoter activity of Drosophila bib gene, particularly in the larval imaginal discs, which are actively proliferating tissues, as well as the adult hindgut. Our results may provide insight into the mechanisms inherent to the regulation of mammalian AQP genes.