<i>N</i>-GLUCURONIDATION OF PERFLUOROOCTANESULFONAMIDE BY HUMAN, RAT, DOG, AND MONKEY LIVER MICROSOMES AND BY EXPRESSED RAT AND HUMAN UDP-GLUCURONOSYLTRANSFERASES

Xu, Lin; Krenitsky, Daria M.; Seacat, Andrew M.; Butenhoff, John L.; Tephly, Thomas R.; Anders, M. W.

doi:10.1124/dmd.106.009399

Cited by 48 publications

(26 citation statements)

References 27 publications

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“…The responsible mechanism must therefore have been metabolism, either to PFOS or a phase II conjugate. Xu et al found that PFOSA is metabolized to an N-glucuronide in isolated hepatic cells, 11,42 but no glucuronide conjugates of PFOSA were detected in this study, consistent with glucuronidation of PFOSA being only a minor metabolic pathway in vivo in rats. 39 Although PFOSA and other PFOS-precursors have been detected in human blood and in wildlife tissues, 1 few studies have investigated the isomer profile of PFOS-precursors in environmental samples.…”

Section: ■ Results and Discussionsupporting

confidence: 93%

Isomer-Specific Biotransformation of Perfluorooctane Sulfonamide in Sprague–Dawley Rats

Ross

Wong

Martin

2012

Environ. Sci. Technol.

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Great variability exists in perfluorooctane sulfonate (PFOS) isomer patterns in human and wildlife samples, including unexpectedly high percentages (e.g., >40%) of branched isomers in human sera. Previous in vitro tests showed that branched PFOS-precursors were biotransformed faster than the corresponding linear isomer. Thus, high percentages of branched PFOS may be a biomarker of PFOS-precursor exposure in humans. We evaluated this hypothesis by examining the isomer-specific fate of perfluorooctane sulfonamide (PFOSA), a known PFOS-precursor, in male Sprague-Dawley rats exposed to commercial PFOSA via food for 77 days (83.0 ± 20.4 ng kg(-1) day(-1)), followed by 27 days of depuration. Elimination half-lives of the two major branched PFOSA isomers (2.5 ± 1.0 days and 3.7 ± 1.2 days) were quicker than for linear PFOSA (5.9 ± 4.6 days), resulting in a depletion of branched PFOSA isomers in blood and tissues relative to the dose. A corresponding increase in the total branched isomer content of PFOS, the ultimate metabolite, in rat serum was not observed. However, a significant enrichment of 5m-PFOS and a significant depletion of 1m-PFOS were observed, relative to authentic electrochemical PFOS. The data cannot be directly extrapolated to humans, due to known differences in the toxicokinetics of PFOS in rodents and humans. However, the results confirm that in vivo exposure to commercially relevant PFOS-precursors can result in a distinct PFOS isomer profile that may be useful as a biomarker of exposure source.

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Section: ■ Results and Discussionsupporting

confidence: 93%

Isomer-Specific Biotransformation of Perfluorooctane Sulfonamide in Sprague–Dawley Rats

Ross

Wong

Martin

2012

Environ. Sci. Technol.

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“…This contrasts with several other enzymes, such as UGT1A3 and UGT2B7, that can catalyze the N-glucuronidation of certain aglycones in addition to other glucuronidation reactions (Green and Tephly, 1998;Zenser et al, 2002;Zhang et al, 2004;Borlak et al, 2006;Xu et al, 2006). This difference in function could be reflected by the primary structure of these enzymes, and an inspection of the amino acid sequences of all the human UGTs has indeed revealed an interesting observation.…”

Section: Discussionmentioning

confidence: 80%

“…Our newly developed analytical method was applied to the determination of nicotine and cotinine glucuronidation rates by UGT1A4 and UGT1A9, enzymes reported previously to catalyze nicotine glucuronidation (Kuehl and Murphy, 2003), and by UGT2B7, an enzyme that is involved in the glucuronidation of many structurally diverse xenobiotics including N-glucuronidation reactions (Zhang et al, 2004;Xu et al, 2006). It is noteworthy that the activity of UGT2B10 was also determined because our preliminary studies with this enzyme showed efficient N-glucuronidation of certain other compounds (Kaivosaari S, Koskinen M, and Finel M, manuscript in preparation).…”

Section: Resultsmentioning

confidence: 99%

Nicotine Glucuronidation and the Human UDP-Glucuronosyltransferase UGT2B10

Kaivosaari¹,

Toivonen²,

Hesse³

et al. 2007

Mol Pharmacol

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Nicotine biotransformation affects the smoking habits of addicted individuals and therefore their health risk. Using an improved analytical method, we have discovered that the human UDP-glucuronosyltransferase (UGT) 2B10, a liver enzyme previously unknown to conjugate nicotine or exhibit considerable activity toward any compound, plays a major role in nicotine inactivation by direct conjugation with glucuronic acid at the aromatic nitrogen atom. The K m value of recombinant UGT2B10 for nicotine (0.29 mM) was similar to that determined for human liver microsomes (0.33 mM), whereas the K m value of UGT1A4 for nicotine was almost 10-fold greater (2.4 mM). UGT2B10 was also more active than UGT1A4 in N-glucuronidation of cotinine (oxidative nicotine metabolite), whereas UGT2B7 exhibited only low nicotine glucuronidation activity and was essentially inactive toward cotinine. UGT1A9 did not glucuronidate nicotine or cotinine. Quantitative reverse transcription-polymerase chain reaction showed that UGT2B10 mRNA was exclusively expressed in human liver, whereas UGTs 1A4 and 2B7 were expressed at comparable, although somewhat lower, levels in liver and several other extrahepatic tissues, including kidney and intestine. These findings for UGT2B10 (but not for UGT1A4 and UGT2B7) were mirrored by human tissue activities because nicotine and cotinine glucuronidation rates in intestine microsomes were less than 0.1% that of human liver microsomes. These novel findings solve two seemingly separate questions: which UGT is primarily responsible for nicotine glucuronidation in human liver, and what conjugation reactions are catalyzed by UGT2B10.Nicotine is not carcinogenic by itself and might even have some beneficial therapeutic effects in some neurological diseases. Nonetheless, it is the major perpetrator of tobaccorelated diseases because nicotine addiction drives smokers to pursue the habit despite the known health hazards. Nicotine concentration in the blood increases sharply during cigarette smoking and then decreases rapidly because of metabolism and clearance, driving the addicted individual to reach for another cigarette. Hence, better understanding of nicotine metabolism can assist the development of treatments to reduce the health risks associated with nicotine addiction.Cytochrome P450 monooxygenase 2A6 (CYP2A6) catalyzes nicotine oxygenation and plays an important role in nicotine metabolism (Hukkanen et al., 2005;Nakajima and Yokoi, 2005). However, there is more to nicotine metabolism than CYP2A6 because both nicotine and its primary oxidation metabolite, cotinine, undergo direct N-glucuronidation at the aromatic nitrogen (Fig.

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“…The difference in the method of microsome preparation may influence glucuronidation activities. However, in past studies, species differences of glucuronidation activities have been assessed with microsomes prepared by different methods (Xu et al, 2006;Cai et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

et al. 2014

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UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various drugs. Although experimental rodents are used in preclinical studies to predict glucuronidation and toxicity of drugs in humans, species differences in glucuronidation and drug-induced toxicity have been reported. Humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) were recently developed. In this study, acyl-glucuronidations of etodolac, diclofenac, and ibuprofen in liver microsomes of hUGT1 mice were examined and compared with those of humans and regular mice. The kinetics of etodolac, diclofenac, and ibuprofen acyl-glucuronidation in hUGT1 mice were almost comparable to those in humans, rather than in mice. We further investigated the hepatotoxicity of ibuprofen in hUGT1 mice and regular mice by measuring serum alanine amino transferase (ALT) levels. Because ALT levels were increased at 6 hours after dosing in hUGT1 mice and at 24 hours after dosing in regular mice, the onset pattern of ibuprofen-induced liver toxicity in hUGT1 mice was different from that in regular mice. These data suggest that hUGT1 mice can be valuable tools for understanding glucuronidations of drugs and druginduced toxicity in humans.

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N-GLUCURONIDATION OF PERFLUOROOCTANESULFONAMIDE BY HUMAN, RAT, DOG, AND MONKEY LIVER MICROSOMES AND BY EXPRESSED RAT AND HUMAN UDP-GLUCURONOSYLTRANSFERASES

Cited by 48 publications

References 27 publications

Isomer-Specific Biotransformation of Perfluorooctane Sulfonamide in Sprague–Dawley Rats

Isomer-Specific Biotransformation of Perfluorooctane Sulfonamide in Sprague–Dawley Rats

Nicotine Glucuronidation and the Human UDP-Glucuronosyltransferase UGT2B10

Glucuronidation of Drugs and Drug-Induced Toxicity in HumanizedUDP-Glucuronosyltransferase 1Mice

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