Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Impact on cancer therapy

Alexandra Maier-Salamon, Theresia Thalhammer, Gottfried Reznicek, Michaela Böhmdorfer, I. Zupkó, Alexander Hartl, Walter Jaeger

Research output: Contribution to journalArticle

Abstract

The metabolism of 9-aminocamptothecin (9-AC) was investigated in human and rat liver microsomes. In both species 9-AC was almost exclusively biotransformed to dihydroxy-9-AC (M1) and monohydroxy-9-AC (M2). The enzymatic efficiencies of the formation of M1 and M2 ( Vmax/Km) were 1.7- and 2.7-fold higher in rat than in human liver microsomes indicating species-related differences in 9-AC hydroxylation. Incubation in the presence of human recombinant cytochrome P450 (CYP) enzymes demonstrated that the formation of M1 and M2 is mainly catalyzed by CYP3A4 and only to a minor extent by extrahepatic CYP1A1. The predominant role of CYP3A4 was further supported by a dramatic inhibition of metabolite formation in the presence of the CYP3A4 substrates troleandomycin and ketoconazole. Experiments conducted in isolated perfused rat livers further demonstrated that biliary excretion of 9-AC, M1 and M2 during 60 min of perfusion was pronounced and accounted for 17.7±2.59, 0.05±0.01 and 2.75±0.14% of total 9-AC applied to the liver, respectively. In summary, this study established that CYP3A-dependent hydroxylation is the main metabolic pathway for 9-AC in rat and human liver, which have to be taken into consideration during cancer therapy of patients.

Original languageEnglish
Pages (from-to)877-886
Number of pages10
JournalInternational Journal of Oncology
Volume45
Issue number2
DOIs
Publication statusPublished - 2014

Fingerprint

9-aminocamptothecin
Topoisomerase I Inhibitors
Cytochrome P-450 CYP3A
Neoplasms
Liver Microsomes
Therapeutics
Hydroxylation
Cytochrome P-450 Enzyme System
Liver
Troleandomycin
Cytochrome P-450 CYP1A1
Ketoconazole
Metabolic Networks and Pathways

Keywords

  • 9-aminocamptothecin
  • Biliary excretion
  • Cytochrome P450
  • Hepatic metabolism
  • Human liver microsomes
  • Phase i metabolism

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin : Impact on cancer therapy. / Maier-Salamon, Alexandra; Thalhammer, Theresia; Reznicek, Gottfried; Böhmdorfer, Michaela; Zupkó, I.; Hartl, Alexander; Jaeger, Walter.

In: International Journal of Oncology, Vol. 45, No. 2, 2014, p. 877-886.

Research output: Contribution to journalArticle

Maier-Salamon, Alexandra ; Thalhammer, Theresia ; Reznicek, Gottfried ; Böhmdorfer, Michaela ; Zupkó, I. ; Hartl, Alexander ; Jaeger, Walter. / Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin : Impact on cancer therapy. In: International Journal of Oncology. 2014 ; Vol. 45, No. 2. pp. 877-886.
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AU - Böhmdorfer, Michaela

AU - Zupkó, I.

AU - Hartl, Alexander

AU - Jaeger, Walter

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AB - The metabolism of 9-aminocamptothecin (9-AC) was investigated in human and rat liver microsomes. In both species 9-AC was almost exclusively biotransformed to dihydroxy-9-AC (M1) and monohydroxy-9-AC (M2). The enzymatic efficiencies of the formation of M1 and M2 ( Vmax/Km) were 1.7- and 2.7-fold higher in rat than in human liver microsomes indicating species-related differences in 9-AC hydroxylation. Incubation in the presence of human recombinant cytochrome P450 (CYP) enzymes demonstrated that the formation of M1 and M2 is mainly catalyzed by CYP3A4 and only to a minor extent by extrahepatic CYP1A1. The predominant role of CYP3A4 was further supported by a dramatic inhibition of metabolite formation in the presence of the CYP3A4 substrates troleandomycin and ketoconazole. Experiments conducted in isolated perfused rat livers further demonstrated that biliary excretion of 9-AC, M1 and M2 during 60 min of perfusion was pronounced and accounted for 17.7±2.59, 0.05±0.01 and 2.75±0.14% of total 9-AC applied to the liver, respectively. In summary, this study established that CYP3A-dependent hydroxylation is the main metabolic pathway for 9-AC in rat and human liver, which have to be taken into consideration during cancer therapy of patients.

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