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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Biomimetic Metabolism of Kaurenoic Acid Validated by Microsomal Reactions

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Fernandes, Eduardo Felipe Alves [1, 2] ; de Oliveira, Anderson R. M. [3] ; Barros, Valeria Priscila [4] ; Guaratini, Thais [2] ; Lopes, Norberto Peporine [1]
Total Authors: 5
[1] Univ Sao Paulo, NPPNS, Dept Ciencias Biomol, Fac Ciencias Farmaceut Ribeirao Preto, Ave Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil
[2] Lychnoflora Pesquisa & Desenvolvimento Prod Nat L, Rua Angelo Mestriner 263, Ribeirao Preto, SP - Brazil
[3] Univ Sao Paulo, Dept Quim, Fac Filosofia Ciencias & Letras Ribeirao Preto, BR-14040901 Ribeirao Preto, SP - Brazil
[4] Univ Fed Sergipe, Dept Quim, Ave Vereador Olimpio Grande S-N, BR-49500000 Itabaiana, SE - Brazil
Total Affiliations: 4
Document type: Journal article
Web of Science Citations: 0

The cytochrome P450 is a remarkable family of enzymes with widespread occurrence in animals and plants. In humans, they catalyze phase I metabolism reactions, such as oxidations and hydroxylations, playing a significant role in xenobiotics detoxification. Although mechanistic details of the catalytic cycle of cytochrome P450 are known, and human isoforms have their crystal structure solved, mimicking cytochrome P450 reactions using in vitro systems is still challenging. For this reason, biological assays using isolated enzymes or microsomal fractions are typically required to study the oxidative metabolism of new drugs before approval by regulatory agencies. Here we demonstrate that a series of metalloporphyrin catalysts generate the same oxidative product in vitro as a liver microsomal assay. The bioactive diterpene kaurenoic acid was chosen as a substrate model because it is a component of widely used phytomedicines in Brazil, such as guaco syrups and copaiba waxes. We evaluated the influence of reaction parameters such as catalyst type, oxygen donor type, solvent, and catalyst concentration on substrate consumption. Three products had their structures proposed by mass spectrometry, and among them, a dihydroxylated oxidation product was detected as a major metabolite after liver microsomal biotransformation and using porphyrin catalysts. We envision that the use of metalloporphyrins could be a useful strategy for biomimetic oxidation of kaurenic terpenes. (AU)

FAPESP's process: 14/50265-3 - Distribution and metabolism of natural and synthetic xenobiotics: from the comprehension of reactional process to tissue imaging generation
Grantee:Norberto Peporine Lopes
Support type: BIOTA-FAPESP Program - Thematic Grants
FAPESP's process: 13/17658-9 - Development and validation of chromatographic and electrophoretic methods for subsequent application in studies of in vitro metabolism and biotransformation - phase 2
Grantee:Anderson Rodrigo Moraes de Oliveira
Support type: Regular Research Grants