Rapid oxidation of ring methyl groups is the primary mechanism of biotransformation of gemfibrozil by the fungus Cunning
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ORIGINAL PAPER
Rapid oxidation of ring methyl groups is the primary mechanism of biotransformation of gemWbrozil by the fungus Cunninghamella elegans Su-Il Kang · Seo-Young Kang · Robert A. Kanaly · Eunjung Lee · Yoongho Lim · Hor-Gil Hur
Received: 1 February 2009 / Revised: 8 April 2009 / Accepted: 14 April 2009 / Published online: 30 April 2009 © Springer-Verlag 2009
Abstract The hypolipidemic agent gemWbrozil (GEM), which has been studied for its metabolism in humans and animals, was investigated to elucidate its primary metabolism by Cunninghamella elegans. The fungus produced ten metabolites (FM1–FM9 and FM6⬘) from the biotransformation of GEM. Based on LC/MS/MS and NMR analyses, a major metabolite, FM7, was identiWed as 2⬘-hydroxymethyl GEM. FM6 was considered to be 5⬘-hydroxymethyl GEM, after comparison of results LC/MS, LC/MS/MS, and UV absorption spectra to FM7. The combined concentration of FM6 and FM7 was found to increase up to 0.83 mM by day 2, and then decreased gradually with incubation time, followed by a noticeable increase in the biotransformation product, FM1, up to 0.86 mM by day 15. NMR analyses conWrmed that FM1 was 2⬘,5⬘-dihydroxymethyl GEM. Further minor oxidations of the aromatic ring and carboxylic acid intermediates were also detected. Based Communicated by Erko Stackebrandt. S.-I. Kang · S.-Y. Kang · H.-G. Hur International Environmental Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea R. A. Kanaly Department of Genome Systems, Faculty of Bionanoscience, Yokohama City University, Yokohama 236-002, Japan E. Lee · Y. Lim Department of Bioscience and Biotechnology, and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea H.-G. Hur (&) Department of Environmental Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea e-mail: [email protected]
upon these Wndings, the major fungal metabolic pathway for GEM is likely to occur via production of 2⬘,5⬘-dihydroxymethyl GEM from 2⬘-hydroxymethyl GEM. These relatively rapid and diverse biotransformations of GEM by C. elegans suggest that depending upon conditions, it may also follow a similar biodegradation fate when released into the natural environment. Keywords Cunninghamella elegans · Fungal metabolism · GemWbrozil · Hydroxylation · Hypolipidemic
Introduction GemWbrozil (GEM) is a lipid-regulating agent that has been widely used in the treatment of hypertriglyceridemia and hypercholesterolemia by lowering the plasma concentrations of triglycerides and total plasma cholesterol through peroxisome proliferator-activated receptor- (PPAR). Its metabolism has been extensively studied in humans, rats, hamsters and dogs for example (Curtis et al. 1985; Dix et al. 1999; Ishikawa et al. 2004; Nakagawa et al. 1991; Murai et al. 2004; Okerholm et al. 1976; Randinitis et al. 1984; Thomas et al. 1999; Xia et al. 2003). In human metabolism, GEM is metabolized with the production of diverse urinary metabolites, including the acyl
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