Nitroreduction of flutamide by Cunninghamella elegans NADPH: Cytochrome P450 reductase

• Published in: Biochemistry and biophysics reports 2022-03, Vol.29, p.101209-101209, Article 101209
• Main Authors: Khan, Mohd Faheem, Murphy, Cormac D.
• Format: Article
• Language: English
• Subjects: Biotransformation; CYP reductase; Drug metabolism; Microbial model
• ISSN: 2405-5808; 2405-5808
• DOI: 10.1016/j.bbrep.2022.101209

The microbial model of mammalian drug metabolism, Cunninghamella elegans, has three cytochrome P450 reductase genes in its genome: g1631 (CPR_A), g4301 (CPR_B), and g7609 (CPR_C). The nitroreductase activity of the encoded enzymes was investigated via expression of the genes in the yeast Pichia pastoris X33. Whole cell assays with the recombinant yeast demonstrated that the reductases converted the anticancer drug flutamide to the nitroreduced metabolite that was also produced from the same substrate when incubated with human NADPH: cytochrome P450 reductase. The nitroreductase activity extended to other substrates such as the related drug nilutamide and the environmental contaminants 1-nitronaphthalene and 1,3-dinitronaphthalene. Comparative experiments with cell lysates of recombinant yeast were conducted under aerobic and reduced oxygen conditions and demonstrated that the reductases are oxygen sensitive. •Three cytochrome P450 reductase genes from Cunninghamella elegans were heterologously expressed in Pichia pastoris.•TThe enzymes displayed nitroreductase activity towards flutamide, which is analogous to human cytochrome P450 reductase.•The enzymes are oxygen sensitive, which is also a property shared with the human enzyme.•Other nitro-containing substrates can be reduced by the fungal enzymes.