Biomimetic Metabolism of Kaurenoic Acid Validated by Microsomal Reactions

Autor(es)

Fernandes, Eduardo Felipe Alves ^{[1, 2]} ; de Oliveira, Anderson R. M. ^[3] ; Barros, Valeria Priscila ^[4] ; Guaratini, Thais ^[2] ; Lopes, Norberto Peporine ^[1]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY; v. 30, n. 4 AUG 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 14/50265-3 - Metabolismo e distribuição de xenobióticos naturais e sintéticos: da compreensão dos processos reacionais à geração de imagens teciduais
• Beneficiário: Norberto Peporine Lopes
• Linha de fomento: Auxílio à Pesquisa - Programa BIOTA - Temático
• Processo FAPESP: 13/17658-9 - Desenvolvimento e validação de métodos cromatográficos e eletroforéticos para posterior aplicação em estudos de biotransformação e metabolismo in vitro - fase 2
• Beneficiário: Anderson Rodrigo Moraes de Oliveira
• Linha de fomento: Auxílio à Pesquisa - Regular