Biotransformation of N-Ethyl-N-(2-hydroxyethyl)perfluorooctanesulfonamide by Rat Liver Microsomes, Cytosol, and Slices and by Expressed Rat and Human Cytochromes P450

Abstract

Perfluorooctanesulfonic acid (PFOS) and its derivatives have been used in a range of industrial and commercial applications, including the manufacture of surfactants, adhesives, anticorrosion agents, and insecticides. PFOS is found at detectable concentrations in human and wildlife tissues and in the global environment. N-Substituted perfluorooctanesulfonamides are believed to be degraded to PFOS and, therefore, contribute to the accumulation of PFOS in the environment. N-Ethyl-N-(2-hydroxyethyl)perfluorooctanesulfonamide (N-EtFOSE) is converted to PFOS in experimental animals. The objective of this study was to elucidate the pathways for the biotransformation of N-EtFOSE, which is a major precursor and component of PFOS-based compounds. N-EtFOSE and several putative metabolites were incubated with liver microsomes and cytosol and with liver slices from male Sprague-Dawley rats. Microsomal fractions fortified with NADPH catalyzed the N-deethylation of N-EtFOSE to give N-(2-hydroxyethyl)perfluorooctanesulfonamide (FOSE alcohol) and of FOSE alcohol to give perfluorooctanesulfonamide (FOSA). These N-dealkylation reactions were catalyzed mainly by male rat P450 2C11 and P450 3A2 and by human P450 2C19 and 3A4/5. Rat liver microsomal fractions incubated with UDP-glucuronic acid catalyzed the O-glucuronidation of N-EtFOSE and FOSE alcohol and the N-glucuronidation of FOSA. Cytosolic fractions incubated with NAD(+) catalyzed the oxidation of FOSE alcohol to perfluooctanesulfonamidoacetate (FOSAA). The oxidation of N-EtFOSE to N-ethylperfluorooctanesulfonamidoacetate (N-EtFOSAA) was observed in liver slices but not in cytosolic fractions. FOSA was biotransformed in liver slices to PFOS, albeit at a low rate. These results show that the major pathway for the biotransformation of N-EtFOSE is N-dealkylation to give FOSA. The biotransformation of FOSA to PFOS explains the observation that PFOS is found in animals given N-EtFOSE.

Endocrine, biotransformation, and oxidative stress responses in salmon hepatocytes exposed to chemically induced hypoxia and perfluorooctane sulfonamide (PFOSA), given singly or in combination

“…Herein, we showed that hypoxia increased oxidative stress responses in salmon hepatocytes. In accordance with the present study, previous studies have reported increased oxidative stress response after exposure to PFASs (Arukwe and Mortensen 2011; Slotkin et al 2008, Wågbø et al 2012Xu et al 2004), most likely caused by xenobiotic metabolism and/or increased peroxisomal proliferation (Olufsen et al 2014;Wågbø et al 2012). …”

“…Because of their role in the detoxification and activation of foreign compounds, alterations of hepatic phase I and -II enzymes is important from a toxicological standpoint (Williams et al 1998). In mammalian systems, PFOSA is metabolically degraded to PFOS at a slow rate, but also undergoes enterohepatic circulation and mediate oxidative stress responses (Slotkin et al 2008;Xu et al 2004). Sustained hypoxia is known to cause oxidative stress, due to increased formation of ROS, produced by metabolism and the electron transport chain (Gnaiger et al 1995;Mansfield et al 2005;Nathan and Cunningham-Bussel 2013).…”

Perfluorinated compounds in the Pearl River and Yangtze River of China

“…Among the PFCs, PFOS and PFOA generally accounted for 88-100% and 50-87%, respectively, of the total concentrations of PFASs and PFCAs analyzed. The predominance of PFOS and PFOA may not only be due to the direct discharge of these compounds to the environment during manufacturing processes or uses of related products (Lehmler, 2005;Prevedouros et al, 2006), but also the possibility of degradation of other precursor compounds to these chemicals, which are regarded as the terminal degradation end-products that are persistent and bioaccumulative Tomy et al, 2004;Xu et al, 2004).…”

“…PFCs can also be formed from indirect conversion of their precursor compounds. For example, conversion of N-ethyl perfluorooctane sulfonaminoethanol (N-EtFOSE) and N-ethyl perfluorooctane sulfonamide (N-EtFOSA) to PFOS has been observed in liver microsomes of rats (Xu et al, 2004) and rainbow trout (Tomy et al, 2004), respectively. Fluorotelomer alcohols were also suggested to be the precursor compounds of various perfluorocarboxylic acids (PFCAs) (Dinglasan et al, 2004;Ellis et al, 2004).…”

Synthesis and structure of environmentally relevant perfluorinated sulfonamides

“…Pyridine, which has been used previously as solvent for the synthesis of perfluorooctane-1-sulfonic acid (2,2-dimethoxy-ethyl)-amide from perfluorooctanesulfonyl fluoride 1 [3], was not investigated because it is typically difficult to remove residual pyridine traces. We found that the solvent had little-to-no effect on the overall yield.…”