Removal of diclofenac and mefenamic acid by the white rot fungus Phanerochaete sordida YK-624 and identification of their metabolites after fungal transformation

Abstract

The non-steroidal anti-inflammatory drugs diclofenac (DCF) and mefenamic acid (MFA) were treated with the white rot fungus Phanerochaete sordida YK-624. DCF completely disappeared and MFA decreased by about 90% after 6 days of treatment. It was also confirmed that the fungus almost completely removed the acute lethal toxicity of DCF and MFA towards the freshwater crustacean Thamnocephalus platyurus after 6 days of treatment. Mass spectrometric and (1)H nuclear magnetic resonance analyses demonstrated that two mono-hydroxylated DCFs (4'-hydroxydiclofenac and 5-hydroxydiclofenac) and one di-hydroxylated DCF (4',5-dihydroxydiclofenac) were formed via fungal transformation. The four metabolites of MFA were identified as 3'-hydroxymethylmefenamic acid (mono-hydroxylated MFA), 3'-hydroxymethyl-5-hydroxymefenamic acid (di-hydroxylated MFA), 3'-hydroxymethyl-6'-hydroxymefenamic acid (di-hydroxylated MFA) and 3'-carboxymefenamic acid. These results suggest that hydroxylation catalyzed by cytochrome P450 (CYP) in P. sordida YK-624 may be involved in the elimination and detoxification of DCF and MFA. This notion was further supported by the fact that smaller decreases in DCF and MFA were observed in cultures of P. sordida YK-624 incubated with 1-aminobenzotriazole, a known inhibitor of CYP.

Removal of bisphenol A and diclofenac by a novel fungal membrane bioreactor operated under non-sterile conditions

“…Furthermore, intracellular enzymes, such as the cytochrome P450 enzyme system of fungus, are also reported to be helpful for TrOCs removal (Golan-Rozen et al, 2011), especially, in the context of this study, for diclofenac (Hata et al, 2010).…”

Efficient biotransformation of non-steroid anti-inflammatory drugs by endophytic and epiphytic fungi from dried leaves of a medicinal plant, Plantago lanceolata L.

“…In a study using an ex vivo intestinal model, metabolism inhibitors increased DIC toxicity, and also reduced the generated amount of 4'-OH-DIC, 5-OH-DIC (Niu et al, 2015). Oxydative biotransformation of DIC and MEF also reduced the toxicity against a freshwater crustacean in (Hata et al, 2010). In contrast, during the metabolism of IBU into 1,2-dihydroxy-IBU by Trametes versicolor, increase in toxicity was observed in Microtox bioassay (Marco-Urrea et al, 2009b).…”

“…Several studies have shown the oxidative modification of these drugs. Production of 4',5-dihydroxy-diclofenac, 4',-hydroxy-diclofenac and 5-hydroxy-diclofenac from the NSAID diclofenac by Phanerochaete sordida was reported by (Hata et al, 2010). The same fungus was shown to successfully metabolize mefenamic acid into several oxidized products, like 3-OH-mefenamic acid and 3-COOH-mefenamic acid (Hata et al, 2010).…”

“…Production of 4',5-dihydroxy-diclofenac, 4',-hydroxy-diclofenac and 5-hydroxy-diclofenac from the NSAID diclofenac by Phanerochaete sordida was reported by (Hata et al, 2010). The same fungus was shown to successfully metabolize mefenamic acid into several oxidized products, like 3-OH-mefenamic acid and 3-COOH-mefenamic acid (Hata et al, 2010). The ibuprofen metabolism also consisted of oxidation (hydroxylation) steps in the case of Trametes versicolor, but the final product (1,2-dihydroxyibuprofen) was found to be new, and not previously described in biological systems (Marco-Urrea et al, 2009b).…”

Biodegradation Characteristics of Pharmaceutical Substances by Whole Fungal Culture Trametes versicolor and its Laccase

“…Furthermore, in a recent study by Hata et al, (2010) it was found that degradation of diclofenac and mefenamic acid by white rot fungal culture may be involved in the…”