Mephenytoin, cytochrome

Cytochrome P450 2C19, also termed S-mephenytoin hydroxylase, is a mixed-function oxidase localized in the endoplasmic reticulum which is responsible for the biotransformation of S-mephenytoin, some barbiturates, almost all proton pump inhibitors such as omeprazole, diazepam and others. 

Relling, M.V., Evans, W.E., Fonne-Pfister, R., et al. (1989) Anticancer drugs as inhibitors of two polymorphic cytochrome P450 enzymes, debrisoquin and mephenytoin hydroxylase, in human liver microsomes. Cancer Res. 49, 68-71. 

Cytochrome P450, subfamily lie (mepheny-toin 4-hydroxylase), polypeptide 19 flavo-protein-hnked monooxygenase mephenytoin 4 -hydroxylase microsomal monooxygenase xenobiotic monooxygenase... 

P. (1986) The molecular mechanisms of two common polymorphisms of drug oxidation—evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation. Xenobiotica 16, 449-464. 

Rost KL, Brosicke H, Brockmoller J, Scheffler M, Helge H, Roots I. Increase of cytochrome P450IA2 activity by omeprazole evidence by the 13C-[ A - 3 - m e t h y I ] - c a I fe i ne breath test in poor and extensive metabolizers of S-mephenytoin. Clin Pharmacol Ther 1992 52 170-180. 

Wrighton SA, Stevens JC, Becker GW. Isolation and characterization of human liver cytochrome P4502C19 correlation between 2C19 and S-mephenytoin 4 -hydroxylation. Arch Biochem Biophys 1993 306 240-245. 

Goldstein JA, Blaisdell J. Genetic tests which identify the principal defects in CYP2C19 responsible for the polymorphism in mephenytoin metabolism. In Johnson EF, Waterman MR, eds. Cytochrome P450, Part B Methods in Enzy-mology. San Diego, CA Academic Press, 1996 272 210-218. 

Masimirembwa C, Bertilsson L, Johnansson I, et al. Phenotyping and genotyping of S-mephenytoin hydroxylase (cytochrome P450 2C19) in a Shona population of Zimbabwe. Clin Pharmacol Ther 1995 57 656-661. 

Ko JW, Desta Z, Flockhart DA. Human N-demethylation of (S)-mephenytoin by cytochrome P450s 2C9 and 2B6. Drug Metah Dispos 1998 26 775-778. 

Eap CB, Bondolfi G, Zullino D, Bryois C, Fuciec M, Savary L, Jonzier-Perey M, Baumann P. Pharmacokinetic drug interaction potential of risperidone with cytochrome p450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test. Ther Drug Monit 2001 23(3) 228-31. 

Figure 4 Polymorphic drug oxidations by cytochrome P450. A, substrates subject to debrisoquine/sparteine polymorphism. R(+)-bufuralol is I -hydroxyl-ated by P450-IID6 the S(—)-enantiomer undergoes hydroxylation at the 2- and 4-positions debrisoquine is hydroxylated at the prochiral C4-atom to S(+)-hydroxy-debrisoquine sparteine metabolism by P450-IID6 consists of N-oxidation. B, substrates subject to hydantoin polymorphism (4 -hydroxylation). Extensive metabolizers convert S(+)-mephenytoin and -nirvanol to the 4 -hydroxy derivative (indicated by the arrow). Similarly, EMs metabolize the prochiral drug phenytoin to R(+)-4 -hydroxyphenytoin. = chiral center.

Meyer, U A., Gut, I Kronback, T., Scoda, C., Meier, U. T, Catin, T., and Dayer, P. (1986). The Molecular Mechanism of Two Common Polymorphisms of Drug Oxidation-—Evidence for Functional Changes in Cytochrome P450 Isozymes Catalyzing Bufuralol and Mephenytoin Oxidation, Xenobiotka, 16 449-464. 

Relling, M, V, Ayoma, T, Gonzales, E J., and Meyer, U. A, (1990), Tolbutamide and Mephenytoin Hydroxylation by Human Cytochrome-P450s in the CYP2Cu Subfamily, /. Pharmacol. Exp. Ther., 252 442-447. 

Figure 11 Representation of epoxide hydrolase reactions and the metabolism of mephenytoin by cytochrome P450 (CYP), epoxide hydrolase (EH) and dihydrodiol dehy-drogenase (DHD).

Gut J, Meier UT, Catin T, et al. Mephenytoin-type polymorphism of drug oxidation purification and characterization of a human liver cytochrome P-450 isozyme catalyzing microsomal mephenytoin hydroxylation. Biochim Biophys Acta I986 884(3) 435—47. 

Human liver microsomal cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism. Purification and characterization of two similar forms involved in the reaction. J. Biol. Chem. 261, 909-921. 

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