Bufuralol hydroxylation

Hanna IH, Kim MS, Guengerich FP. Heterologous expression of cytochrome P450 2D6 mutants, electron transfer, and catalysis of bufuralol hydroxylation the role of aspartate 301 in structural integrity. Arch Biochem Biophys 2001 393 255-61. 

Gut, J., Gasser, R., Dayer, P., Kronbach, T., Catin, T., and Meyer, U. A. (1984) Dehrisoquine-type polymorphism of drug oxidation purification from human liver of a cytochrome P450 isozyme with high activity for bufuralol hydroxylation. FEES Lett. 173 (2), 287-290. 

Dayer, P. Leemann, T. Kupfer, A. Kronbach, T. Meyer, U.A. Stereo- and regioselectivity of hepatic oxidation in man—effect of the debrisoquine/ sparteine phenotype on bufuralol hydroxylation. Eur. J. Clin. Pharmacol. 1986, 31, 313-318. 

Yamazaki H, Guo Z, Persmark M, Mimura M, In-oue K, Guengerich FP, ShimadaT (1994) Bufuralol hydroxylation by cytochrome P450 2D6 and 1A2 enzymes in human liver microsomes. Mol Pharmacol 46 568-577... 

As an example of the first type of chiral effect, metabolism of the drug bufuralol may be considered. Hydroxy la tion in the V position only occurs with the (+) isomer, whereas for hydroxylation in positions 4 and 6, the (—) isomer is the preferred substrate (Fig. 5.3). Glucuronidation of the side chain hydroxyl group is specific for the (+) isomer. A further complication in human subjects is that the 1-hydroxylation is under genetic control, being dependent on the debrisoquine hydroxylator status (see below). The selectivity for the isomers for the hydroxylations is virtually abolished in poor metabolizers. 

Figure 5.3 The hydroxylation of the drug bufuralol. The arrows show (A) the site of V hydroxylation and (B) the site of glucuronidation.

As with the hydroxylation of bufuralol, the hydroxylation is stereo-selective. Thus, only S-mephenytoin undergoes aromatic 4-hydroxy lation, and only this route is affected by the polymorphism. The R isomer undergoes N-demethylation. Poor metabolizers may suffer an exaggerated central response when given therapeutic doses (Fig. 5.29). 

Praeksaritanont T, Dwyer LM, Cribb AE. (+)-Bufuralol 1 -hydroxylation activity in human and rhesus monkey intestine and liver. Biochem Pharmacol 1995 50(9) 1521-1525. 

Crespi, C.L., Chang, T.K., and Waxman, D.J. CYP2D6-dependent bufuralol 1 -hydroxylation assayed by reverse-phase ion-pair high-performance liquid chromatography with fluorescence detection. Methods Mol. Biol. 2006, 320, 121-125. 

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.

The oxidative clearance of the lipophilic drugs, metoprolol, timolol, and bufuralol, is influenced by the debri-soquine hydroxylation gene locus, resulting in polymorphic metabolism (233). This might result in an... 

As an example of the first type of chiral effect, metabolism of the drug bufuralol may be considered. Hydroxylation in the V position only occurs with the (+) isomer whereas for hydroxylation in the 4 and... 

Gut, X, T. Catin, P. Dayer, T. Kronbach, U. Zanger, and U.A. Meyer (1986). Debrisoquine/sparteine-type polymorphism of drug oxidation Purification and characterization of two functionally different human liver cytochrome P-450 isozymes involved in impaired hydroxylation of the prototype substrate bufuralol. J. Biol. Chem. 261, 11734-11743. 

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