Comparison of cytochrome P-450 species which catalyze the hydroxylations of the aromatic ring of estradiol and estradiol 17-sulfate

Watanabe, Kimitsuna; Takanashi, Kaori; Imaoka, Shingi; Funae, Yoshihiko; Kawano, Sumie; Inoue, Katsuhiro; Kamataki, Tetsuya; Takagi, Hidetoshi; Yoshizawa, Itsuo

doi:10.1016/0960-0760(91)90087-l

Cited by 21 publications

(17 citation statements)

References 33 publications

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“…In a recent publication, Mutlib and colleagues (1999) showed that a metabolite of the human immunodeficiency virus reverse transcriptase inhibitor efavirenz was first sulfonated and subsequently glucuronidated to a glucuronide-sulfate diconjugate. Evidence that sulfate conjugates can serve as substrates for further metabolism has also been previously reported for the sulfonated steroid estradiol, which is further hydroxylated (Watanabe and Yoshizawa, 1982;Watanabe et al, 1991). Glucuronidated compounds have also been shown to undergo further metabolic modifications; for example, Tang and Abbott (1996) demonstrated that the glucuronide of the 2,4-diene metabolite of valproic acid undergoes further conjugation with glutathione to form a glucuronide-glutathione diconjugate.…”

Section: Discussionmentioning

confidence: 90%

Conjugation of Desmethylnaproxen in the Rat—A Novel Acyl Glucuronide-Sulfate Diconjugate as a Major Biliary Metabolite

Jäggi¹,

Addison²,

King³

et al. 2002

Drug Metab Dispos

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This paper is available online at http://dmd.aspetjournals.org ABSTRACT:The nonsteroidal anti-inflammatory drug naproxen is primarily metabolized in humans by acyl glucuronidation to form naproxen acyl glucuronide and by O-dealkylation to form 6-O-desmethylnaproxen (DMN). DMN contains both carboxy and phenolic groups and has been shown to form acyl glucuronide and sulfate conjugates. This project aimed to investigate whether DMN formed a phenolic glucuronide and diglucuronide(s) (with both the carboxy and phenolic groups glucuronidated). Male Sprague-Dawley rats (300-350 g) with exteriorized bile flow were dosed i.v. with DMN at 50 mg/kg. Four major DMN-related peaks were detected in bile by high-performance liquid chromatography (HPLC) analysis at 225 nm, including the known acyl glucuronide and sulfate conjugates. Selective hydrolyses using acidic and alkaline conditions and digestion with ␤-glucuronidase allowed tentative identification of the two unknown peaks as the phenolic glucuronide of DMN and a novel acyl glucuronide-sulfate diconjugate of DMN (i.e., formed by sulfonation of the phenolic group and glucuronidation of the carboxy group). The identities were confirmed by liquid chromatography-tandem mass spectrometry analysis of individual HPLC fractions. Total recovery of the DMN dose was approximately 80%, with the sulfate conjugate (50%) and unchanged DMN (10%) being excreted predominantly in urine and the acyl glucuronide (10%), phenolic glucuronide (6%), and acyl glucuronide-sulfate diconjugate (4%) being excreted predominantly or exclusively in bile. No evidence for a diglucuronide metabolite of DMN was found in either bile or urine of the DMN-dosed rats.The salicylate derivative diflunisal, a nonsteroidal anti-inflammatory drug (NSAID 1 ), has both carboxy and phenolic functional groups and forms acyl glucuronide, phenolic glucuronide, and sulfate monoconjugates as major metabolites in humans and animals (Tocco et al., 1975;Lin et al., 1985;Loewen et al., 1986;Dickinson et al., 1989). In previous work, we have reported the additional formation of small quantities of quasi "diglucuronides" of diflunisal in the rat and the perfused rat liver (King and Dickinson, 1991;Wang and Dickinson, 1998). The yield of diglucuronides was greater if the preformed biosynthetic acyl glucuronide was administered and much greater again when the acyl migration rearrangement isomers were administered. By contrast, no diglucuronides were formed after administration of the phenolic glucuronide of diflunisal. Interestingly, the mixture of diglucuronides appeared to comprise the phenolic glucuronides of the 2-, 3-, and possibly 4-O-positional isomers of the acyl glucuronides (King and Dickinson, 1991). Whether any "real" diglucuronide (i.e., the phenolic glucuronide of the biosynthetic acyl glucuronide) was formed was equivocal. These results brought forth interesting questions about the presence of recognition/transport/metabolism processes pertaining to real (i.e., biosynthetic) acyl glucuronides versus "look-alikes" (i.e...

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Section: Discussionmentioning

confidence: 90%

Conjugation of Desmethylnaproxen in the Rat—A Novel Acyl Glucuronide-Sulfate Diconjugate as a Major Biliary Metabolite

Jäggi¹,

Addison²,

King³

et al. 2002

Drug Metab Dispos

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“…It has been shown that the estrogen glucuronide acts as one of the precursor of E2 in vivo and inhibition of β-glucuronidase-mediated hydrolysis of estrogen glucuronides suppressed the estrogen-dependent mammary tumor promotion in Sprague-Dawley rat models (62,63). It should be noted that estrogen sulfates or glucuronides can also be hydroxylated in steroid A-ring in liver as well as extrahepatic target cells (64). Deconjugation of hydroxylated conjugates may lead to catechol estrogen metabolites, which are partly responsible for estrogen-mediated toxic effects.…”

Section: Metabolism Of Estrogenmentioning

confidence: 99%

Dual roles of estrogen metabolism in mammary carcinogenesis

Chang

2011

BMB Reports

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A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review. [BMB reports 2011; 44(7): 423-434]

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“…It should also be noted that certain of these P450s have been shown to hydroxylate other sex steroids as well (Waxman et al, 1991;Guengerich, 1995). The lack of inhibition of 16a-hydroxylation of 17/3-estradiol by fenitrothion is surprising since in the rat, this pathway appears to be catalyzed by enzymes which also catalyze 2-hydroxylation (2A1, 2C11, and 2D1) (Cheng and Schenkman, 1984;Watanabe et al, 1991;Martucci and Fishman, 1993). Therefore, the results of the current study suggest that in the mouse, 16a-hydroxylation and 2-hydroxylation of 17/3-estradiol are catalyzed by different P450s.…”

Section: Discussionmentioning

confidence: 74%

“…The present study suggests that fenitrothion is oxidatively desulfurated by the same mouse hepatic P450s that hydroxylate 17/3-estradiol at the 2 and 4 positions. While P450-dependent 17/3-estradiol metabolism by mouse liver has not been extensively characterized, hepatic 2-and 4-hydroxylation of 17/3-estradiol in the rat can be catalyzed by CYP1A1/1A2, 2A1/2A2, 2C11, 2D, 3A1/3A2, and 1A2 and 2A1/2A2, respectively (Cheng and Schenkman, 1984;Watanabe et al, 1991;Martucci and Fishman, 1993). In humans, it has been reported that 1A2, 2C9, 1 A3, 1A4, 1A5, and 4B1 hydroxylate 17/3-estradiol at the 2 position, while 1A2, 3A3, 3A4, 3A5, 1B1, and 4B1 hydroxylate 17/3-estradiol at the 4 position (Aoyama et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

The Effects of the Phosphorothioate Insecticide Fenitrothion on Mammalian Cytochrome P450-Dependent Metabolism of Estradiol

Berger

Sultatos

1997

Toxicol Sci

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Comparison of cytochrome P-450 species which catalyze the hydroxylations of the aromatic ring of estradiol and estradiol 17-sulfate

Cited by 21 publications

References 33 publications

Conjugation of Desmethylnaproxen in the Rat—A Novel Acyl Glucuronide-Sulfate Diconjugate as a Major Biliary Metabolite

Conjugation of Desmethylnaproxen in the Rat—A Novel Acyl Glucuronide-Sulfate Diconjugate as a Major Biliary Metabolite

Dual roles of estrogen metabolism in mammary carcinogenesis

The Effects of the Phosphorothioate Insecticide Fenitrothion on Mammalian Cytochrome P450-Dependent Metabolism of Estradiol

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