Mephenytoin hydroxylase

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. 

Helsby, N.A., Ward, S.A., Howells, R.E. and Breckenridge, A.M. (1990) in vitro metabolism of the biguanide antimalarials in human liver microsomes evidence for a role of the mephenytoin hydroxylase (P450 MP)... 

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. 

R) -mephenytoin is slowly N-demethylated to nirvanol, an active metabolite. "Poor metabolizers," however, appear to totally lack the stereospecific (S)-mephenytoin hydroxylase activity, so both... 

Wienkers LC, Wurden CJ, Storch E, et al. Formation of (R)-8-hydroxywarfarin in human liver - microsomes - a new metabolic marker for the (S)-mephenytoin hydroxylase, P4502C19. Drug Metab Dispos 1996 24 610-614. 

Andersson T, Miners JO, Veronese ME, et al. Diazepam metabolism by human liver microsomes is mediated by both (5)-mephenytoin hydroxylase and CYP3A isoforms. Br J Cbn Pharmacol 1994 38 131-137. 

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. 

Somogyi AA, Reinhard HA, Bochner F. Pharmacokinetic evaluation of proguanil a probe phenotyping drug for the mephenytoin hydroxylase polymorphism. Br J Clin Pharmacol 1996 41 175-179. 

Birkett DJ, Rees D, Andersson T, et al. In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylase. Br J Clin Pharmacol 1994 37 413 -20. 

CYP2C19 (mephenytoin hydroxylase) is also associated with marked interethnic differences. This enzyme metabolizes diazepam and several antidepressants (Pi and Gray 1998). Between 2% and 10% of whites have little or no activity of this enzyme, whereas 15%-25% of Asians maybe PMs (Horaietal. 1989 Kupfer and Preisig 1984 Pi and Gray 1998). In addition, there is also evidence of polymorphism among EMs, with some Asian EMs having a form of the enzyme with less activity than that of the form commonly found in Caucasian EMs (Sjoqvist et al. 1997). 

Wright JD, Helsby NA, Ward SA. The role of S-mephenytoin hydroxylase (CYP2C19) in the metabolism of the antimalarial biguanides. Br J Chn Pharmacol 1995 39 441-4. 

Zhou HH. CYP2C19 genotype determines enzyme activity and inducibility of S-mephenytoin hydroxylase. Clin Chim Acta 2001 313 203-8. 

The PPIs are completely metabolized and excreted by renal and facal pathways (Tab. 1). Of the cytochrome P-450 (CYP) isoforms involved, CYP 2C19 (i5-mephenytoin hydroxylase) is the most important, followed by CYP 3A4 [20, 33] (Fig. 3), whose role becomes more significant in people with reduced or absent expression of CYP 2C19 [34]. CYP3A4 seems to be more involved in formation of primary lansoprazole metabolites however, subsequent processing is dominated by CYP 2C19 [35]. 

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