Use of microorganisms for the study of drug metabolism: An update

Clark, Alice M.; Hufford, Charles D.

doi:10.1002/med.2610110503

Cited by 84 publications

(58 citation statements)

References 71 publications

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“…Since, microbial systems have been successfully used to mimic mammalian metabolism of drugs, 6) we attempted to generate decursin metabolites prospectively 7) with the help of such models. Initial screening of decursin with ten fungal strains showed the formation of two metabolites by seven cultures.…”

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confidence: 99%

Microbial Metabolism. Part 8. The Pyranocoumarin, Decursin

Herath

Reddy

Khan

2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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Section: )mentioning

confidence: 99%

Microbial Metabolism. Part 8. The Pyranocoumarin, Decursin

Herath

Reddy

Khan

2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…It can be used to synthesize chemical structures that are difficult to obtain by other means (24) and as a model of mammalian metabolism due to the similarity between mammalian and microbial cytochrome P 450 enzyme systems (1,2,4,5,12). The metabolism of cinobufagin in rat liver microsomes produced at least six metabolites (32), resulting primarily from deacetylation at C-16 and epimerization of 3-OH via a 3-keto intermediate.…”

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Specific 12β-Hydroxylation of Cinobufagin by Filamentous Fungi

Guo

et al. 2004

Appl Environ Microbiol

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Biotransformation of natural products has great potential for producing new drugs and could provide in vitro models of mammalian metabolism. Microbial transformation of the cytotoxic steroid cinobufagin was investigated. Cinobufagin could be specifically hydroxylated at the 12␤-position by the fungus Alternaria alternata. Six products from a scaled-up fermentation were obtained by silica gel column chromatography and reversed-phase liquid chromatography and were identified as 12␤-hydroxyl cinobufagin, 12␤-hydroxyl desacetylcinobufagin, 3-oxo-12␤-hydroxyl cinobufagin, 3-oxo-12␤-hydroxyl desacetylcinobufagin, 12-oxo-cinobufagin, and 3-oxo-12␣-hydroxyl cinobufagin. The last five products are new compounds. 12␤-Hydroxylation of cinobufagin by A. alternata is a fast catalytic reaction and was complete within 8 h of growth with the substrate. This reaction was followed by dehydrogenation of the 3-hydroxyl group and then deacetylation at C-16. Hydroxylation at C-12␤ also was the first step in the metabolism of cinobufagin by a variety of fungal strains. In vitro cytotoxicity assays suggest that 12␤-hydroxyl cinobufagin and 3-oxo-12␣-hydroxyl cinobufagin exhibit somewhat decreased but still significant cytotoxic activities. The 12␤-hydroxylated bufadienolides produced by microbial transformation are difficult to obtain by chemical synthesis.Bufadienolides are steroids with a characteristic ␣-pyrone ring at the C-17 position; they have cardiotonic, blood pressure-stimulating, antiviral, and local anesthetic activities (20). More than 300 bufadienolides have been isolated from natural sources including plants and animals (15,23). These compounds have been reported to have significant antitumor activities (9,19,31,33). Cinobufagin (compound I) is a bufadienolide with a 14␤,15␤-epoxy ring, originally isolated as a major component of the traditional Chinese drug, Chan'Su (also called toad venom or toad poison), which is prepared from the skin secretions of giant toads (10). Cinobufagin can induce apoptosis and elevate intracellular Ca 2ϩ levels (13,14). Against cancer cells it has a 50% inhibitory concentration (IC 50 ) of approximately 10 Ϫ8 mol/liter (30). Unfortunately, it is poorly soluble in water and is toxic to humans; therefore, analogs with improved pharmaceutical properties, such as those obtained from plant cell suspension cultures (27,29), are needed before this compound can be utilized effectively in a clinical setting.Microbial transformation is an important tool for structural modification of organic compounds, especially natural products with complicated structures (17,22). It can be used to synthesize chemical structures that are difficult to obtain by other means (24) and as a model of mammalian metabolism due to the similarity between mammalian and microbial cytochrome P 450 enzyme systems (1,2,4,5,12). The metabolism of cinobufagin in rat liver microsomes produced at least six metabolites (32), resulting primarily from deacetylation at C-16 and epimerization of 3-OH via a 3-keto intermediate. The exact s...

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“…Since there have been no reports on the mammalian metabolism of betulinic acid, a prospective approach was used to study its metabolism by utilizing microorganisms as in vitro model systems. Fungi, bacteria, and yeasts have been utilized successfully as in vitro models to mimic and predict the metabolic fate of drugs and other xenobiotics in mammalian systems (7,9,15,16,28). Studies have shown that many of the mammalian phase I and phase II biotransformation reactions, including hydroxylation, N oxidation, O and N dealkylation, dehydrogenation, and glucuronide and sulfate conjugation reactions, occur in microbial systems as well (27).…”

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Biotransformation of the Antimelanoma Agent Betulinic Acid by Bacillus megaterium ATCC 13368

Chatterjee

Kouzi

Pezzuto

et al. 2000

Appl Environ Microbiol

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Microbial transformation of the antimelanoma agent betulinic acid was studied. The main objective of this study was to utilize microorganisms as in vitro models to predict and prepare potential mammalian metabolites of this compound. Preparative-scale biotransformation with resting-cell suspensions of Bacillus megaterium ATCC 13368 resulted in the production of four metabolites, which were identified as 3-oxo-lup-20(29)-en-28-oic acid, 3-oxo-11␣-hydroxy-lup-20(29)-en-28-oic acid, 1␤-hydroxy-3-oxo-lup-20(29)-en-28-oic acid, and 3␤,7␤,15␣-trihydroxy-lup-20(29)-en-28-oic acid based on nuclear magnetic resonance and high-resolution mass spectral analyses. In addition, the antimelanoma activities of these metabolites were evaluated with two human melanoma cell lines, Mel-1 (lymph node) and Mel-2 (pleural fluid).Betulinic acid (compound 1, Fig. 1), 3␤-hydroxy-lup-20(29)-en-28-oic acid, is a pentacyclic lupane type of triterpene that is widely distributed in the plant kingdom (8,19). Betulinic acid has been shown to exhibit a variety of biological activities, including inhibition of human immunodeficiency virus (HIV) replication in H9 lymphocyte cells (11), blockage of HIV type 1 entry into cells (20), and inhibition of DNA polymerase ␤ (18). Synthetic derivatives of betulinic acid have also been investigated as specific inhibitors of HIV type 1 (11-13). In addition, betulinic acid has been reported to be a melanomaspecific cytotoxic agent in both in vitro cell culture and in vivo studies (24). The antitumor activity of this compound is mediated by the induction of apoptosis, as demonstrated by a variety of cellular responses (24). Due to its high level of antitumor activity and lack of toxicity, betulinic acid is an attractive and promising new lead compound for use against human melanoma and is currently undergoing preclinical development for treatment or prevention of malignant melanoma.An essential part of the preclinical development of a drug is elucidation of its mammalian metabolism. Since there have been no reports on the mammalian metabolism of betulinic acid, a prospective approach was used to study its metabolism by utilizing microorganisms as in vitro model systems. Fungi, bacteria, and yeasts have been utilized successfully as in vitro models to mimic and predict the metabolic fate of drugs and other xenobiotics in mammalian systems (7,9,15,16,28). Studies have shown that many of the mammalian phase I and phase II biotransformation reactions, including hydroxylation, N oxidation, O and N dealkylation, dehydrogenation, and glucuronide and sulfate conjugation reactions, occur in microbial systems as well (27). The biochemical bases for this parallelism in metabolic reactions lie in the similarity between mammalian and microbial enzyme systems, such as cytochrome P450 monooxygenases and copper oxidases. These studies, which have been extensively reviewed in the literature, highlighted the potential value of microbial transformations as a powerful tool for mimicking and predicting mammalian biotransformations ...

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Use of microorganisms for the study of drug metabolism: An update

Cited by 84 publications

References 71 publications

Microbial Metabolism. Part 8. The Pyranocoumarin, Decursin

Microbial Metabolism. Part 8. The Pyranocoumarin, Decursin

Specific 12β-Hydroxylation of Cinobufagin by Filamentous Fungi

Biotransformation of the Antimelanoma Agent Betulinic Acid by Bacillus megaterium ATCC 13368

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