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

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 (V(max)/K(m)) 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.

Transcriptome-Wide Identification of Cytochrome P450s and GSTs from Spodoptera exigua Reveals Candidate Genes Involved in Camptothecin Detoxification

“…It has been documented that its complex metabolism involves many proteins. In humans, cytochrome P450 monooxygenases (P450s or CYPs) have been documented as being involved in the degradation of CPTs, especially P450 isoforms 1A1, 3A4, and 3A5 (CYP1A1, CYP3A4, CYP3A5) [1][2][3]. In recent years, based on the knowledge of the metabolism of CPTs by CYPs, a promising CPT delivery scaffold-CPT-encapsulated PLGA (poly(lactic-co-glycolic acid), PLGA-CPT) nanoparticles-was prepared to improve the bioavailability of CPTs and reduce their side effects [4].…”