Uptake and Metabolism of Human Pharmaceuticals by Fish - A Case Study with the Opioid Analgesic Tramadol.

This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Environmental science & technology, copyright © American Chemical Society after peer review. To access the final edited and published work see https://doi.org/10.1021/acs.est.7b03441Recent species-extrapolation approaches to predict the potential effects of pharmaceuticals present in the environment on wild fish are based on the assumption that pharmacokinetics and metabolism in humans and fish are comparable. To test this hypothesis, we exposed fathead minnows to the opiate pro-drug tramadol and examined uptake from the water into the blood and brain, and metabolism of the drug into its main metabolites. We found that plasma concentrations could be predicted reasonably accurately based on the lipophilicity of the drug, once the pH of the water was taken into account. The concentrations of the drug and its main metabolites were higher in the brain than in the plasma, and the observed brain/plasma concentration ratios were within the range of values reported in mammalian species. This fish species was able to metabolise the pro-drug tramadol into the highly active metabolite O-desmethyl tramadol and the inactive metabolite N-desmethyl tramadol in a similar manner to mammals. However, we found that concentration ratios of O-desmethyl tramadol to tramadol were lower in the fish than values in most humans administered the drug. Our pharmacokinetic data of tramadol in fish help bridge the gap between widely available mammalian pharmacological data and potential effects on aquatic organisms, and highlight the importance of understanding drug uptake and metabolism in fish to enable the full implementation of predictive toxicology approaches.We would like to thank members of the Ecotoxicology Research Group, Brunel University London, particularly J. Walker, N. Brodigan, and A. Ferreira for fish husbandry, and T. Thrupp, E. Lawton, and A. Baynes for fish sampling. The research at Brunel University London was internally funded by the university. This study was also supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) to a project on Joint Usage/Research Center– Leading Academia in Marine and Environment Pollution Research (LaMer), and Research Fellowships from the Japan Society for the Promotion of Science (JSPS) for Young Scientists in Japan (PD) provided to R. Tanoue (26·2800), Grants in Bid (KAKENHI) for Scientific Research (A) (25257403), Scientific Research (A) (16H01784). This study was also funded by the Sasakawa Scientific Research Grant from The Japan Science Society

Maternal estrogen controls retinoic acid metabolism and signaling in early vertebrate development

Fertilized eggs of lower vertebrates contain substantial amounts of steroidal hormones such as estrogen transferred from mother during oogenesis. However, molecular roles for maternal estrogen in the early embryonic development are largely unknown. Here we show that maternal estrogen and estrogen receptor-α modulate retinoic acid (RA) metabolism and RA-responsive gene expression in medaka embryos. Treatments with excess estradiol, an anti-estrogen (tamoxifen), overexpression or knockdown of estrogen receptor-α (ERα) resulted in misregulation of RA-related gene expression such as raldh2 (retinalaldehyde dehydrogenase), cyp26a1 (RA hydroxylase), fgf8 (fibroblast growth factor), rarα (RA receptor-α), and ahr1 (aryl hydrocarbon receptor). We propose that maternal estrogen/ERα plays a critical role in the feedback control of in vivo level of RA and that it also activates RA signaling for the development of hindbrain and vasculatures. This is the first report demonstrating that maternal estrogen supports successful embryonic development by controlling RA metabolism and signaling in early vertebrate embryos.Supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan

UGT Xenobiotic metabolizing activity and genetic evolution in Pinniped species

There are various interspecies differences in xenobiotic-metabolizing enzymes. It is known that cats show slow glucuronidation of drugs such as acetaminophen and strong side effects due to the UGT1A6 pseudogene. Recently, the UGT1A6 pseudogene was found in the Northern elephant seal and Otariidae was suggested to be UGT1A6-deficient. From the results of measurements of uridine diphosphate-glucuronosyltransferase (UGT) activity using liver microsomes, the Steller sea lion, Northern fur seal, and Caspian seal showed UGT activity toward 1-hydroxypyrene and acetaminophen as low as in cats, which was significantly lower than in rat and dog. Furthermore, UGT1A6 pseudogenes were found in Steller sea lion and Northern fur seal, and all Otariidae species were suggested to have the UGT1A6 pseudogene. The UGT1 family genes appear to have undergone birth-and-death evolution based on a phylogenetic and synteny analysis of the UGT1 family in mammals including Carnivora. UGT1A2-1A5 and UGT1A7-1A10 are paralogous genes to UGT1A1 and UGTA6, respectively, and their numbers were lower in cat, ferret and Pacific walrus than in human, rat, and dog. Felidae and Pinnipedia, which are less exposed to natural xenobiotics such as plant-derived toxins due to their carnivorous diet, have experienced fewer gene duplications of xenobiotic-metabolizing UGT genes, and even possess UGT1A6 pseudogenes. Artificial environmental pollutants and drugs conjugated by UGT are increasing dramatically, and their elimination to the environment can be of great consequence to cat and Pinnipedia species, whose low xenobiotic glucuronidation capacity makes them highly sensitive to these compounds

Table S2

List of DEGs Which were Affected by 4-OH-CB107 in Dose-Dependent Manne

Occurrence and Source of Chlorinated Polycyclic Aromatic Hydrocarbons (Cl-PAHs) in Tidal Flats of the Ariake Bay, Japan

In this study, we hypothesize that natural photochemical reactions of polycyclic aromatic hydrocarbons (PAHs) in tidal flats are responsible for the occurrence of chlorinated polycyclic aromatic hydrocarbons (Cl-PAHs). This study aims to survey the impact of photochemical reactions using a combination of field surveys and lab-scale experiments. Concentrations and profiles of PAHs and Cl-PAHs in road dust and sediments collected from seven tunnels and two watersheds, respectively, were determined. In the lab-scale experiments, anthracene was irradiated with ultraviolet (UV) light under various salinity conditions. No detectable Cl-PAHs were found in the road dust. However, Cl-PAHs were detected in the sediments from 700 to 6.1 × 10³ pg g^–1 and specifically from downstream sites. 2-Monochloroanthracene (2-Cl-ANT) and 9,10-dichloroanthracene (9,10-di-Cl-ANT) were dominant in the sediments. In the Domen River watershed, the ∑Cl-PAHs and the salinity showed a significant positive correlation (<i>p</i> < 0.01) in the sediments, while such a correlation was not found for PAHs. 2-Cl-ANT, 9-monochloroanthracene, and 9,10-di-Cl-ANT were identified as transformation products in the UV irradiation experiments. Production of these Cl-PAHs was dependent on the solution salinity. These results support our hypothesis, and we conclude that photochemical reactions significantly contribute to the occurrence of Cl-PAHs in the studied tidal flats

Data from: Effects of 4-Hydroxy-2,3,3',4',5-pentachlorobiphenyl (4-OH-CB107) on liver transcriptome in rats: implication in the disruption of circadian rhythm and fatty acid metabolism

Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) have been detected in tissues of both wild animals and humans. Several previous studies have suggested adverse effects of OH-PCBs on the endocrine and nervous systems in mammals. However, there have been no studies on transcriptome analysis of the effects of OH-PCBs, and thus, the whole picture and mechanisms underlying the adverse effects induced by OH-PCBs are still poorly understood. We therefore investigated the mRNA expression profile in the liver of adult male Wistar rats treated with 4-hydroxy-2,3,3',4',5-pentachlorobiphenyl (4-OH-CB107) to explore the genes responsive to OH-PCBs and to understand the potential effects of the chemical. Next-generation RNA sequencing analysis revealed changes in the expression of genes involved in the circadian rhythm and fatty acid metabolism, such as nuclear receptor subfamily 1, group D, member 1 (Nr1d1), aryl hydrocarbon receptor nuclear translocator-like protein 1 (Arntl), cryptochrome circadian clock 1 (Cry1), and enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase (Ehhadh), in 4-OH-CB107-treated rats. In addition, biochemical analysis of the plasma revealed a dose-dependent increase in the leucine aminopeptidase (LAP), indicating the onset of liver damage. These results suggest that OH-PCB exposure may induce liver injury as well as disrupt the circadian rhythm and peroxisome proliferator-activated receptor (PPAR)-related fatty acid metabolism

Interspecies differences in cytochrome P450-mediated metabolism of neonicotinoids among cats, dogs, rats, and humans

Neonicotinoid insecticides are used for agricultural and non-agricultural purposes worldwide. Pets are directly exposed to neonicotinoids in veterinary products and through environmental contamination. Cytochrome P450 (CYP) is among the most significant xenobiotic metabolizing enzymes that oxidizes several chemicals, including neonicotinoids. However, CYP activities and metabolite compositions of neonicotinoid metabolites are unknown in most domesticated pet species. Our objectives were to reveal the differences in metabolites of neonicotinoids (imidacloprid, clothianidin, and acetamiprid) and CYP activities among common pet species (cats and dogs), humans, and rats. The results indicated that the CYP-mediated neonicotinoid metabolism was different depending on species and each neonicotinoid. Among these four species, the kinetics of imidacloprid metabolism indicated that rats have the highest rate of oxidation of imidacloprid to 4OH-imidacloprid, while the greatest enzyme kinetics of imidacloprid metabolism to 5OH-imidacloprid were found in rats and humans. Clothianidin was rapidly metabolized to 1-methyl-3-nitroguanidine and dm-clothianidin in rats, but cats and humans showed the lowest formation of dm-clothianidin. CYP activities in metabolism of acetamiprid to dm-acetamiprid and N-acetyl-acetamiprid were determined to be significantly higher in humans compared to other species. However, further studies should be targeted at identifying the differences in hepatic metabolism of neonicotinoids in these species using recombinant CYP enzymes

Lead exposure in raptors from Japan and source identification using Pb stable isotope ratios

Lead (Pb) poisoning is widespread among raptors and water birds. In Japan, fragments of Pb ammunition are still found in endangered eagles although more than 10 years have passed since legislation regarding use of Pb ammunition was introduced. This study was performed to investigate Pb exposure in raptors from various locations in Japan. We measured hepatic and renal Pb concentrations and hepatic Pb isotope ratios of Steller's sea eagles (Haliaeetus pelagicus), white-tailed sea eagles (Haliaeetus albicilla), golden eagles (Aquila chrysaetos), and 13 other species (total 177 individuals) that were found dead, as well as blood samples from three eagles found in a weakened state during 1993-2015 from Hokkaido (northern part), Honshu (the main island), and Shikoku (a southern island) of japan. In the present study in Hokkaido, one quarter of the sea eagles showed a high Pb concentration, suggesting exposure to abnormally high Pb levels and Pb poisoning. Pb isotope ratios indicated that endangered Steller's sea eagle and white-tailed sea eagle were poisoned by Pb ammunition that was used illegally in Hokkaido. In other areas of Japan, both surveillance and regulations were less extensive than in Hokkaido, but Pb poisoning in raptors was also noted. Therefore, Pb poisoning is still a serious problem in raptors in various areas of Japan due to accidental ingestion of materials containing Pb, especially Pb ammunition. (C) 2017 Published by Elsevier Ltd

Tissue distribution and characterization of feline cytochrome P450 genes related to polychlorinated biphenyl exposure

Cats have been known to be extremely sensitive to chemical exposures. To understand these model species' sensitivity to chemicals and their toxicities, the expression profiles of xenobiotic-metabolizing enzymes should be studied. Unfortunately, the characterization of cytochrome P450 (CYP), the dominant enzyme in phase I metabolism, in eats has not extensively been studied. Polychlorinated biphenyls (PCBs) are known as CYP inducers in animals, but the information regarding the PCB-induced CYP expression in cats is limited. Therefore, in the present study, we aimed to elucidate the mRNA expression of the CYP1-CYP3 families in the cat tissues and to investigate the CYP mRNA expression related to PCB exposure. In cats, the greatest abundance of CYP1-CYP3 (CYP1A2, CYP2A13, CYP2C41, CYP2D6, CYP2E1, CYP2E2, CYP2F2, CYP2F5, CYP2J2, CYP2U1, and CYP3A132) was expressed in the liver, but some extrahepatic isozymes were found in the kidney (CYP1A1), heart (CYP1B1), lung (CYP2B11 and CYP2S1) and small intestine (CYP3A131). In cats, CYP1A1, CYP1A2 and CYP1B1 were significantly upregulated in the liver as well as in several tissues exposed to PCBs, indicating that these CYPs were distinctly induced by PCBs. The strong correlations between 3,3',4,4'-tetrachlorobiphenyl (CB77) and CYP1A1 and CYP1B1 mRNA expressions were noted, demonstrating that CB77 could be a potent CYP1 inducer. In addition, these CYP isoforms could play an essential role in the PCBs biotransformation, particularly 3-4 Cl-PCBs, because a high hydroxylated metabolite level of 3-4 Cl-OH-PCBs was observed in the liver

Plant Uptake of Pharmaceutical Chemicals Detected in Recycled Organic Manure and Reclaimed Wastewater

Land application of recycled manure produced from biosolids and reclaimed wastewater can transfer pharmaceutical chemicals to terrestrial environments, giving rise to potential accumulation of these residues in edible plants. In this study, the potential for plant uptake of 13 pharmaceutical chemicals, and the relation between the accumulation features within the plant and the physicochemical properties were examined by exposing pea and cucumber to an aqueous solution containing pharmaceutical chemicals. Ten of 13 compounds tested were detected in plant leaves and stems. Comparison of the plant uptake characteristics and the octanol–water partition coefficient of pharmaceutical chemicals showed that compounds with an intermediate polarity such as carbamazepine and crotamiton could be easily transported to plant shoots. Moreover, these results suggest the possibility of highly hydrophilic pharmaceutical chemicals such as trimethoprim and sulfonamides to be accumulated in plant roots owing to their low permeability in root cell membranes