Hydroxylation of the thiophene ring by hepatic monooxygenases. Evidence for 5-hydroxylation of 2-aroylthiophenes as a general metabolic pathway using a simple UV-visible assay.

  title={Hydroxylation of the thiophene ring by hepatic monooxygenases. Evidence for 5-hydroxylation of 2-aroylthiophenes as a general metabolic pathway using a simple UV-visible assay.},
  author={Evelyne Neau and Patrick M. Dansette and V I Andronik and Daniel Mansuy},
  journal={Biochemical pharmacology},
  volume={39 6},
Thiophene derivatives as new mechanism-based inhibitors of cytochromes P-450: inactivation of yeast-expressed human liver cytochrome P-450 2C9 by tienilic acid.
TA exhibited all of the characteristics of a mechanism-based inactivator for P 450 2C9 and 2C10 enzymes and could be a starting point for the appearance of anti-P450 2C antibodies detected in patients treated with TA and suffering from immunoallergic hepatitis.
New biological reactive intermediates: metabolic activation of thiophene derivatives.
This work has shown that the major oxidized metabolites of severaI2-aroylthiophenes, such as tienilic acid, were derived from 5-hydroxylation of their thiophene ring (Neau et ai., 1990).
Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9.
The goal of the work presented in this article was to identify the reactive metabolites of TA and TAI by the characterization of products derived from P450 2C9-mediated oxidation and found that TAI was oxidized to two different types of reactive intermediates that ultimately lead to two types of products, a pair of hydroxythiophene/thiolactone tautomers and an S-oxide dimer.
Human-liver cytochromes P-450 expressed in yeast as tools for reactive-metabolite formation studies. Oxidative activation of tienilic acid by cytochromes P-450 2C9 and 2C10.
The results suggest the important role of P450 2C9 in the oxidative metabolism of tienilic acid in human liver and indicate that the 5-hydroxylation reaction could be a useful marker for P450 1C9 activity and underline the interest of human liver P450s expressed in yeast as tools for studying the formation of reactive metabolites.
New Biological Reactive Intermediates
It has been shown that the major oxidized metabolites of several 2-aroylthiophenes, such as tienilic acid (Mansuy et al., 1984) were derived from 5-hydroxylation of their thiophene ring.
Interaction of new sulfaphenazole derivatives with human liver cytochrome p450 2Cs: structural determinants required for selective recognition by CYP 2C9 and for inhibition of human CYP 2Cs.
A series of new derivatives of sulfaphenazole (SPA) were synthesized in order to further explore CYP 2C9 active site and to determine the structural factors explaining the selectivity of SPA for CYP2C9 within the human P450 2C subfamily.


Cytochrome P-450 monooxygenase activities in human and rat liver microsomes.
The monooxygenase activities, the sensitivity to in vitro alpha-naphthoflavone and metyrapone, the results of steroid metabolism, and slab gel electrophoresis are strong indications for multiplicity of human liver cytochrome P-450.
Further structural analysis of urinary metabolites of suprofen in the rat.
  • Y. Mori, Y. Sakai, S. Baba
  • Chemistry
    Drug metabolism and disposition: the biological fate of chemicals
  • 1984
The urinary metabolites of 2-(4-(2-thienylcarbonyl)phenyl)propionic acid (suprofen, S) in rats were analyzed by radio-GC, GC/MS, or 1H NMR technique. Radio-GC analysis of trimethylsilylated materials
The metabolism of thiophen in the rabbit and the rat.
One mercapturic acid was concluded on the basis of mass spectrometric measurements, infra-red spectroscopy and chemical properties to be a premercaptoric acid, viz. 3-hydroxy-2,3-dihydro-2-thienylmercapturic Acid.
Absorption, excretion and metabolism of tiquizium bromide in dogs, and relationship between pharmacological effect and plasma levels of unchanged drug.
The time-course of the inhibitory effect of tiquizium bromide on stomach contraction correlated well with the plasma levels of unchanged drug after intraduodenal administration.
Synthese d'un diuretique marque au carbone 14: Acide dichloro‐2,3 [thenoyl‐2 (14C = 0)]‐4 phenoxy acetique (D.C.I. acide tiénilique)
2-Thenoic acid (14C = 0) 1 is prepared in 75 % radioactive yield by carbonation with 14CO2 of 2-thienyL-magnesium bromide. Boiling of 1 with oxalyl chloride gives rise to 2-thenoylchloride (14CO)
Metabolism of tenoxicam in rats.
The structures of six metabolites of tenoxicam in rats (2 mg/kg, orally), elucidated by physicochemical analyses or the reverse-isotope dilution method, were 5'-hydroxytenoxicam (5% dose),
Syntheses of deuterated phenylpropionic acid derivatives.
2-(4-(2-Thienylhydroxymethyl)phenyl) propionic acid (I), 2-(4-carboxyphenyl) propionic acid (II), 2-(4-(5-hydroxy-2-thienylcarbonyl)phenyl)propionic acid (III) were labeled with multiple-deuterium
Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug.
It is shown that among the macromolecules present in human adult liver microsomes, one protein called cytochrome P-450-8 is specifically recognized by most sera of patients containing anti-LKM2 antibodies but not by control serum, suggesting a possible mechanism for the appearance of anti-organelle antibodies in a drug-induced hepatitis.