![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
ME Veronese, ME McManus, P Laupattarakasem, JO Miners and DJ Birkett
Department of Clinical Pharmacology, School of Medicine, Flinders University of South Australia, Bedford Park, Adelaide.
Tolbutamide hydroxylation has been investigated in human, rabbit and rat liver microsomes and by six purified forms of hepatic rabbit cytochromes P-450. These studies were carried out to investigate whether an appropriate animal model could be developed for the human cytochrome(s) P-450 metabolizing tolbutamide. Selective induction was used in rats and rabbits to indicate the isozymes primarily responsible for tolbutamide hydroxylation in these species. Microsomal tolbutamide hydroxylase activity was significantly induced only by phenobarbital pretreatment in the rat which induces P-450 forms b (P-450IIB1) and/or e (P-450IIB2). Only pretreatment of rabbits with rifampicin, which induces cytochrome P-450 form 3c (P-450IIIA6), significantly increased the microsomal hydroxylation of tolbutamide. However, the increase in tolbutamide hydroxylase activity in rifampicin-induced microsomes (congruent to 50%) appears low compared to known levels of induction of P-450IIIA6 following rifampicin pretreatment (5-10-fold). These data suggest that P-450IIIA6 is at least partially involved in tolbutamide hydroxylation in rabbit liver but that other form(s) may be relatively more important. Reconstitution experiments with six purified forms of rabbit cytochrome P-450 indicated that the highest activity occurred with P-450IIIA6 (form 3c). As isozymes from different gene families or subfamilies appeared to metabolize tolbutamide in the three species studied, catalytic similarities between the P-450s with respect to inhibition was further investigated in microsomes using sulfaphenazole, alpha-naphthoflavone and mephenytoin. These studies showed that the catalytic characteristics in relation to inhibition differ markedly between species. Hence, it appears that the animal model approach is not likely to be successful in the identification and characterization of the cytochrome P-450 form(s) metabolizing tolbutamide in humans.
This article has been cited by other articles:
|
|
 |
|
  Y. Shi, D. D. Ku, R. Y. K. Man, and P. M. Vanhoutte Augmented Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxations Attenuate Endothelial Dysfunction in Femoral and Mesenteric, but Not in Carotid Arteries from Type I Diabetic Rats J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 276 - 281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Komatsu, K. Ito, Y. Nakajima, S.-i. Kanamitsu, S. Imaoka, Y. Funae, C. E. Green, C. A. Tyson, N. Shimada, and Y. Sugiyama Prediction of in Vivo Drug-Drug Interactions between Tolbutamide and Various Sulfonamides in Humans Based on in Vitro Experiments Drug Metab. Dispos., April 1, 2000; 28(4): 475 - 481. [Abstract] [Full Text]
|
|
|
|
|
|
R. F. Tyndale, Y. Li, N.-Y. Li, E. Messina, S. Miksys, and E. M. Sellers Characterization of Cytochrome P-450 2D1 Activity in Rat Brain: High-Affinity Kinetics for Dextromethorphan Drug Metab. Dispos., August 1, 1999; 27(8): 924 - 930. [Abstract] [Full Text]
|
|
|
|
|
|
S. O. Mueller, H. Stopper, and W. Dekant Biotransformation of the Anthraquinones Emodin and Chrysophanol by Cytochrome P450 Enzymes. Bioactivation to Genotoxic Metabolites Drug Metab. Dispos., June 1, 1998; 26(6): 540 - 546. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
