In Vitro Glucuronidation of the Antibacterial Triclocarban and Its Oxidative Metabolites

Schebb, Nils Helge; Franze, Bastian; Maul, Ronald; Ranganathan, Anupama; Hammock, Bruce D.

doi:10.1124/dmd.111.042283

Cited by 24 publications

(27 citation statements)

References 31 publications

(57 reference statements)

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“…TPPU shows good metabolic stability when incubated with primary rat hepatocytes. It is interesting that apparently no direct phase II conjugation by liver glucuronosyltransferases takes place, though the direct N -glucuronidation has been described for the structurally similar triclocarban 38 . Moreover, TPPU seems to be stable by phase I metabolism since 90% of TPPU was remained in the medium of primary rat hepatocytes after 20 h of incubation.…”

Section: Discussionmentioning

confidence: 99%

Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Ostermann¹,

Herbers²,

Willenberg³

et al. 2015

Prostaglandins & Other Lipid Mediators

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Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5 mg TPPU/L with 0.2% PEG400), TPPU’s blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in the tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high levels and thusmakes chronic sEH inhibition studies possible.

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Section: Discussionmentioning

confidence: 99%

Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Ostermann¹,

Herbers²,

Willenberg³

et al. 2015

Prostaglandins & Other Lipid Mediators

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“…It is difficult to extrapolate from the observed formation rate in vitro to the generation of metabolites in tissues in vivo. TCC conversion to both oxidative metabolites and N-glucuronides is substantially underpredicted by in vitro microsomal incubations (Baumann et al, 2010;Schebb et al, 2012b). This low predictability is likely related to the poor water solubility of the compound, 142 nM (Snyder et al, 2010), causing a low effective concentration in the assays.…”

Section: ) These Are Likely the [M-h]mentioning

confidence: 99%

“…Showering with antibacterial soap results in the absorption of ;0.6% of the applied amount of TCC (Schebb et al, 2011b). Several studies have shown that TCC is extensively metabolized in fish, rodents, monkeys, and humans, leading to several phase I and phase II metabolites (Baumann et al, 2010;Schebb et al, 2012b).…”

Section: Introductionmentioning

confidence: 99%

“…The main phase 1 metabolites in all species are monohydroxylated-TCC derivatives bearing the hydroxyl group ortho to the aniline group, namely 29-OH-TCC and 69-OH-TCC (Birch et al, 1978;Baumann et al, 2010;Schebb et al, 2012b). In addition, hydroxylation in the meta position (39-OH-TCC) and substitution of a chlorine atom by a hydroxyl group occurs, yielding 3,4-dichloro-49-hydroxycarbanilide (DHC) [for the structures of metabolites see Schebb et al (2011a)].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, hydroxylation in the meta position (39-OH-TCC) and substitution of a chlorine atom by a hydroxyl group occurs, yielding 3,4-dichloro-49-hydroxycarbanilide (DHC) [for the structures of metabolites see Schebb et al (2011a)]. All hydroxylated metabolites undergo extensive phase II conjugation by UDP-glucuronosyl transferases (Schebb et al, 2012b). Further oxidation of 29OH-TCC, 69OH-TCC, and DHC can generate reactive quinone imines, which can covalently bind to glutathione, and small proteins, as shown in an electrochemistry-liquid chromatography-mass spectrometry (EC-LC-MS) approach to mimic formation of reactive metabolites (Baumann et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Activation of the Antibacterial Agent Triclocarban by Cytochrome P450 1A1 Yielding Glutathione Adducts

et al. 2014

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Triclocarban (3,4,49-trichlorocarbanilide; TCC) is an antibacterial agent used in personal care products such as bar soaps. Small amounts of chemical are absorbed through the epidermis. Recent studies show that residues of reactive TCC metabolites are bound covalently to proteins in incubations with keratinocytes, raising concerns about the potential toxicity of this antimicrobial agent. To obtain additional information on metabolic activation of TCC, this study characterized the reactive metabolites trapped as glutathione conjugates. Incubations were carried out with 14 C-labeled TCC, recombinant CYP1A1 or CYP1B1, coexpressed with cytochrome P450 reductase, glutathione-S-transferases (GSH), and an NADPHgenerating system. Incubations containing CYP1A1, but not 1B1, led to formation of a single TCC-GSH adduct with a conversion rate of 1% of parent compound in 2 hours. Using high-resolution mass spectrometry and diagnostic fragmentation, the adduct was tentatively identified as 3,4-dichloro-39-glutathionyl-49-hydroxycarbanilide. These findings support the hypothesis that TCC is activated by oxidative dehalogenation and oxidation to a quinone imine. Incubations of TCDD-induced keratinocytes with 14 C-TCC yielded a minor radioactive peak coeluting with TCC-GSH. Thus, we conclude that covalent protein modification by TCC in TCDDinduced human keratinocyte incubations is mainly caused by activation of TCC by CYP1A1 via a dehalogenated TCC derivative as reactive species.

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Metabolism of the antibacterial triclocarban by human epidermal keratinocytes to yield protein adducts

Schebb¹,

Buchholz

Hammock

et al. 2012

J Biochem & Molecular Tox

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Previous studies of triclocarban suggest that its biotransformation could yield reactive metabolites that form protein adducts. Since the skin is the major route of triclocarban exposure, present work examined this possibility in cultured human keratinocytes. The results provide evidence for considerable biotransformation and protein adduct formation when cytochrome P450 activity is induced in the cells by TCDD, a model Ah receptor ligand. Since detecting low adduct levels in cells and tissues is difficult, we utilized the novel approach of accelerator mass spectrometry for this purpose. Exploiting the sensitivity of the method, we demonstrated that a substantial portion of triclocarban forms adducts with keratinocyte protein under the P450 inducing conditions employed.

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In Vitro Glucuronidation of the Antibacterial Triclocarban and Its Oxidative Metabolites

Cited by 24 publications

References 31 publications

Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Metabolic Activation of the Antibacterial Agent Triclocarban by Cytochrome P450 1A1 Yielding Glutathione Adducts

Metabolism of the antibacterial triclocarban by human epidermal keratinocytes to yield protein adducts

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