O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4.

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Relling MV, Nemec J, Schuetz EG, Schuetz JD, Gonzalez FJ, Korzekwa KR

O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4.

Mol Pharmacol. 1994 Feb;45(2):352-8.

PubMed ID

8114683 [ View in PubMed

]

Abstract

We previously demonstrated that O-demethylation of the pendant dimethoxyphenol ring of epipodophyllotoxins to produce their respective catechol metabolites is catalyzed by cytochrome(s) P450 in human liver microsomes. Our objective was to identify the specific human cytochrome(s) P450 responsible for catechol formation. Using a panel of prototypical substrates and inhibitors for specific cytochromes P450, we identified substrates for CYP3A4 (midazolam, erythromycin, cyclosporin, and dexamethasone) as inhibitors of catechol formation from both etoposide and teniposide. Dexamethasone inhibition was competitive, with Ki values of 60 and 45 microM for etoposide and teniposide, respectively. In 58 human livers, the correlation coefficients for teniposide catechol formation versus 1'- and 4-hydroxymidazolam formation were 80% and 85%, respectively; for etoposide catechol formation versus 1'- and 4-hydroxymidazolam formation r2 was 83% and 79%, respectively. Teniposide and etoposide catechol formation rates were also significantly correlated with immunodetectable CYP3A (r2 = 49% and 51%, respectively) and not with immunodetectable CYP1A2, 2E1, or 2C8. Finally, cDNAs for human CYP3A4, 3A5, 2A6, 2B6, 2C8, and 2C9 were functionally expressed in HepG2 cells, using a vaccinia viral vector. Teniposide and etoposide catechol formation was catalyzed primarily by 3A4 (15.4 and 40.9 pmol/pmol/hr, respectively) and to a lesser degree by 3A5 (1.94 and 11.3 pmol/pmol/hr, respectively), whereas there was no detectable O-demethylation of epipodophyllotoxins by 2A6, 2B6, 2C8, 2C9, or the control virus alone. Moreover, the relative activities of midazolam hydroxylation, compared with O-demethylation of epipodophyllotoxins, were similar for heterologously expressed 3A4 and for human liver microsomes. We conclude that catechol formation from teniposide and etoposide is primarily mediated by human CYP3A4, making these reactions susceptible to inhibition by prototypical 3A substrates and inhibitors.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Teniposide	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate Inhibitor	Details
Teniposide	Cytochrome P450 3A5	Protein	Humans	No	Substrate	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
Integrate drug-drug interactions in your software
Acenocoumarol Etoposide	The therapeutic efficacy of Acenocoumarol can be increased when used in combination with Etoposide.
Dicoumarol Etoposide	The therapeutic efficacy of Dicoumarol can be increased when used in combination with Etoposide.
Fluindione Etoposide	The therapeutic efficacy of Fluindione can be increased when used in combination with Etoposide.
Phenindione Etoposide	The therapeutic efficacy of Phenindione can be increased when used in combination with Etoposide.
Phenprocoumon Etoposide	The therapeutic efficacy of Phenprocoumon can be increased when used in combination with Etoposide.

Food Interactions

Drug	Interaction
Teniposide	Exercise caution with grapefruit products. Teniposide is a CYP3A4 substrate, and grapefruit inhibits CYP3A4 metabolism, coadministration may increase the serum concentrations of teniposide.
Teniposide	Exercise caution with St. John's Wort. Teniposide is a CYP3A4 substrate, and St. John's Wort induces CYP3A4 metabolism, coadministration may reduce the serum concentrations of teniposide.