Regulation of Drug Conjugate Production by Futile Cycling in Intact Cells

Kauffman, F. C.

doi:10.1007/978-3-642-78429-3_9

Cited by 3 publications

(2 citation statements)

References 26 publications

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“…The majority of the remaining portion of the presumed sulfuric acid ester, in an aqueous environment of tissues, will hydrolyze back to the parent molecule, which may be reutilized for sulfo conjugation as above. In this regard, the benzylic sulfonation of BP tetraol may represent futile cycling as often observed with other sulfate conjugates (20).…”

Section: Resultsmentioning

confidence: 88%

Sulfotransferase-Mediated Activation of 7,8,9,10-Tetrahydro-7-ol, 7,8-Dihydrodiol, and 7,8,9,10-Tetraol Derivatives of Benzo[a]pyrene

Surh¹,

Tannenbaum²

1995

Chem. Res. Toxicol.

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Some hydroxymethyl-substituted polycyclic aromatic hydrocarbons have been shown to be converted to electrophilic, mutagenic, or tumorigenic sulfuric acid ester metabolites by cytosolic sulfotransferase activity in rodent liver. Likewise, certain types of aromatic compounds with a secondary alcoholic functional group at the benzylic position undergo metabolic activation through sulfonation. Enzymatic oxidation of benzo[a]pyrene produces such secondary alcohols as dihydrodiol and tetraol derivatives as primary metabolites. Sulfo conjugation of the benzylic hydroxy group of each of these metabolites is expected to generate an electrophilic sulfuric acid ester capable of covalently binding to DNA, which may contribute to mutagenesis and carcinogenesis by benzo[a]pyrene. Although the model benzo-ring secondary benzyl alcohol, 7-hydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene, covalently bound to DNA and also exerted mutagenicity in the presence of rodent hepatic cytosols and 3'-phosphoadenosine 5'-phosphosulfate, no such sulfotransferase-dependent activation was observed with dihydrodiol or tetraol derivatives of benzo[a]pyrene. Thus, it seems likely that appearance of the adjacent non-benzylic hydroxy functional group(s) in latter metabolites hinders the benzylic sulfonation in these molecules.

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Section: Resultsmentioning

confidence: 88%

Sulfotransferase-Mediated Activation of 7,8,9,10-Tetrahydro-7-ol, 7,8-Dihydrodiol, and 7,8,9,10-Tetraol Derivatives of Benzo[a]pyrene

Surh¹,

Tannenbaum²

1995

Chem. Res. Toxicol.

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“…The activity of β-glucuronidase in the lumen of the ER may lead to futile cycling of Page 10 of 26 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 10 glucuronides [67], which, however, appears to be limited since ß-glucuronidase activity is low. ER-resident β-glucuronidase may also be responsible for hydrolysis of hormone and drug glucuronides in cells, examplified by the hydrolysis of T4 glucuronide.…”

Section: Role Of Er-localized β-Glucuronidase In Glucuronide Dispositionmentioning

confidence: 99%

Topological aspects of oligomeric UDP-glucuronosyltransferases in endoplasmic reticulum membranes: Advances and open questions

Bock

Köhle

2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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Glucuronidation of diflunisal in liver and kidney microsomes of rat and man

Brunelle

Verbeeck

1996

Xenobiotica

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1. The glucuronidation of diflunisal to its phenolic (DPG) and acyl glucuronide (DAG) was measured in vitro using microsomes prepared from rat (n = 4) and human (n = 6) liver and kidney tissue. UGT activities towards bilirubin, 4-nitrophenol and (-)-morphine were also determined. 2. beta-Glucuronidase activity towards phenolphthalein glucuronide was much lower in microsomes prepared from human liver (45.2 +/- 3.1 Fishman Units/mg protein), human kidney (22.0 +/- 3.3 FU/mg), and rat kidney (25.1 +/- 2.5 FU/mg) as compared with rat liver (118.7 +/- 8.8 FU/mg). 3. The formation rate of DAG significantly increased when saccharo-1,4-lactone, a beta-glucuronidase inhibitor, was added to the rat liver microsomal incubation medium. beta-Glucuronidase inhibition, however, had little effect on the formation rate of DAG in human liver microsomes, and no effect in rat and human kidney microsomes. The formation of DPG was not affected by the microsomal beta-glucuronidase activity. 4. Unlike rat kidney microsomes, which only formed DAG, human kidney microsomes formed both diflunisal glucuronides. Formation of both diflunisal glucuronides in human kidney microsomes (Vmax = 0.97 +/- 0.21 and 0.27 +/- 0.07 nmol/min/mg for formation of DAG and DPG respectively) represented 60-70% of the activity found in liver microsomes (Vmax = 1.58 +/- 0.32 and 0.40 +/- 0.08 nmol/min/mg for formation of DAG and DPG respectively). 5. These results demonstrate that the in vitro glucuronidation rate of diflunisal may be affected by the microsomal beta-glucuronidase activity particularly when using rat liver microsomes. Our results also demonstrate that the human kidney has an important UGT-activity towards diflunisal.

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Regulation of Drug Conjugate Production by Futile Cycling in Intact Cells

Cited by 3 publications

References 26 publications

Sulfotransferase-Mediated Activation of 7,8,9,10-Tetrahydro-7-ol, 7,8-Dihydrodiol, and 7,8,9,10-Tetraol Derivatives of Benzo[a]pyrene

Sulfotransferase-Mediated Activation of 7,8,9,10-Tetrahydro-7-ol, 7,8-Dihydrodiol, and 7,8,9,10-Tetraol Derivatives of Benzo[a]pyrene

Topological aspects of oligomeric UDP-glucuronosyltransferases in endoplasmic reticulum membranes: Advances and open questions

Glucuronidation of diflunisal in liver and kidney microsomes of rat and man

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