Genetic Polymorphism of Sparteine/Debrisoquine Oxidation: A Reappraisal

Lennard, M. S.

doi:10.1111/j.1600-0773.1990.tb00830.x

Cited by 55 publications

(28 citation statements)

References 79 publications

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“…It is interesting to note, however, that whereas mutation of either Glu-216 or Asp-301 to Asp and Glu, respectively, can alter the rate and regioselectivity of hydroxylation of debrisoquine, mutation of either residue to a neutral amino acid results in loss of activity. 5 We propose here that both Asp-301 and Glu-216 can act as binding residues for substrates and inhibitors of 2D6. However, the two rotameric states, trans and gaucheϪ, of the aspartate can account for all the various pharmacophoric models, and therefore Glu-216, which sits at the top of the active site cavity, is more likely to act as a recognition residue that attracts basic ligands to the pocket and forms an intermediate binding site prior to the substrate migrating to a "reactive" position within the cavity.…”

Section: Resultsmentioning

confidence: 99%

“…A relatively large number of genetic polymorphisms have been described for 2D6, some of which can either result in rapid or very poor metabolism. One well characterized allelic variant is responsible for a condition known as debrisoquine/sparteine type polymorphism (5,6). This arises as a result of various genetic mutations and affects a significant percentage of the Caucasian population (7).…”

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confidence: 99%

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Crystal Structure of Human Cytochrome P450 2D6

Rowland¹,

Blaney²,

Smyth

et al. 2006

Journal of Biological Chemistry

419

381

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Cytochrome P450 2D6 is a heme-containing enzyme that is responsible for the metabolism of at least 20% of known drugs. Substrates of 2D6 typically contain a basic nitrogen and a planar aromatic ring. The crystal structure of human 2D6 has been solved and refined to 3.0 Å resolution. The structure shows the characteristic P450 fold as seen in other members of the family, with the lengths and orientations of the individual secondary structural elements being very similar to those seen in 2C9. There are, however, several important differences, the most notable involving the F helix, the F-G loop, the B helix, ␤ sheet 4, and part of ␤ sheet 1, all of which are situated on the distal face of the protein. The 2D6 structure has a well defined active site cavity above the heme group, containing many important residues that have been implicated in substrate recognition and binding, including Asp-301, Glu-216, Phe-483, and Phe-120. The crystal structure helps to explain how Asp-301, Glu-216, and Phe-483 can act as substrate binding residues and suggests that the role of Phe-120 is to control the orientation of the aromatic ring found in most substrates with respect to the heme. The structure has been compared with published homology models and has been used to explain much of the reported site-directed mutagenesis data and help understand the metabolism of several compounds. The cytochromes P4504 constitute a superfamily of heme-containing enzymes that catalyze the metabolism of a wide variety of endogenous and xenobiotic compounds. This is accomplished through the activation of molecular oxygen by the heme group, a process that involves the delivery of two electrons to the P450 system followed by cleavage of the dioxygen bond, yielding water and an activated iron-oxygen species (Compound 1), which reacts with substrates through a variety of mechanisms (1). In eukaryotic species, the electron source is a single flavoprotein, the FAD/FMN-containing cytochrome P450 reductase, which binds to the largely basic proximal face of the cytochrome through a number of salt bridges. Of the known human isoforms, cytochrome P450 2D6 is responsible for the metabolism of at least 20% of known drugs (2), with only 3A4 being responsible for a higher (50%) percentage.The cDNA encoding human P450 2D6 has been characterized (3) and subsequently localized to chromosome 22 in the q13.1 region (4). A relatively large number of genetic polymorphisms have been described for 2D6, some of which can either result in rapid or very poor metabolism. One well characterized allelic variant is responsible for a condition known as debrisoquine/sparteine type polymorphism (5, 6). This arises as a result of various genetic mutations and affects a significant percentage of the Caucasian population (7). It results in the defective metabolism of a number of important drug molecules, including debrisoquine, from which the condition got its name. The inability of patients to turn over compounds such as debrisoquine eventually leads to toxic levels of the drug in t...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Crystal Structure of Human Cytochrome P450 2D6

Rowland¹,

Blaney²,

Smyth

et al. 2006

Journal of Biological Chemistry

419

381

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“…Genetically variable activity of cytochrome P450 2D6 (abbreviated CYP2D6, Nebert et al, 1991) results in polymorphic oxidation of debrisoquine, sparteine, dextromethorphan and many other drugs (Eichelbaum & Gross, 1990;Lennard, 1990). The CYP2D6 enzyme is absent in 5 to 10% of the Caucasian population of Europe and North America as a result of CYP2D6 gene deletion or mutations (Gonzalez & Meyer, 1991;Meyer et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone.

Wu¹,

Otton²,

Sproule³

et al. 1993

Brit J Clinical Pharma

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1. In microsomes prepared from three human livers, methadone competitively inhibited the O‐demethylation of dextromethorphan, a marker substrate for CYP2D6. The apparent Ki value of methadone ranged from 2.5 to 5 microM. 2. Two hundred and fifty‐two (252) white Caucasians, including 210 unrelated healthy volunteers and 42 opiate abusers undergoing treatment with methadone were phenotyped using dextromethorphan as the marker drug. Although the frequency of poor metabolizers was similar in both groups, the extensive metabolizers among the opiate abusers tended to have higher O‐demethylation metabolic ratios and to excrete less of the dose as dextromethorphan metabolites than control extensive metabolizer subjects. These data suggest inhibition of CYP2D6 by methadone in vivo as well. 3. Because methadone is widely used in the treatment of opiate abuse, inhibition of CYP2D6 activity in these patients might contribute to exaggerated response or unexpected toxicity from drugs that are substrates of this enzyme.

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“…CYP2D6 is one of the most studied polymorphic genes, and its clinical relevance and allelic frequency have been extensively investigated in different ethnic groups (16,17). To date, no data in the Argentinean population or in porphyric individuals worldwide have been reported.…”

Section: Discussionmentioning

confidence: 99%