The use of microorganisms for the study of drug metabolism

Clark, Alice M.; McChesney, James D.; Hufford, Charles D.

doi:10.1002/med.2610050203

Cited by 96 publications

(48 citation statements)

References 66 publications

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“…The IR spectra were recorded on a ATI Mattson Genesis Series FTIR spectrophotometer. The 1 H-and 13 C-NMR spectra were recorded in DMSO-d 6 on a Bruker AMX-500 spectrometer operating at 500 MHz for 1 H-and at 125 MHz for 13 C-NMR. The HRMS spectra were measured on a Bioapex FT-ICR MS with electrospray ionization.…”

Section: Methodsmentioning

confidence: 99%

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Microbial Transformation of Rubijervine.

Sayed

Dunbar

2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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Veratrum alkaloids are a group of potent hypotensive agents that act by reflex suppression of the cardiovascaular system. 2,3) Rubijervine (1) is one of the most common Veratrum alkaloids possessing the 22,26-epiminocholestane (solanidane) skeleton.4) The interest in Veratrum alkaloids has recently been renewed as they were patented several times during the past few years. [5][6][7][8] The use of steroidal alkaloids including solanidanes and C-nor-D-homosteroidal alkaloids to reverse or inhibit multidrug resistance in cancer or in bacterial, fungal, or parasite infections was reported. 5)The potent regulatory effects of jervane Veratrum alkaloids on hedgehog signaling, modulation of cholesterol biosynthesis and transport, and control of cell proliferation during mandibular arch morphogenesis have recently been reported. [6][7][8] Rubijervine and isorubijervine are suggested to be the plausible biogenetic precursors of cevanine and other C-nor-D-homosteroids. 9) Rubijervine is classified as a possible carcinogen for humans, based on its high tg a value when evaluated by the DC polarography method in anhydrous N, N-dimethylformamide. 10) The antimicrobial activity of rubijervine and other Veratrum alkaloids against Pityrosporum ovale, Trichophyton mentagrophytes, and Saccharomyces cerevisiae and against the basidiomycetes Polstictus versicolor has been reported. 11,12) Metabolism studies have been used successfully as model systems to predict metabolic pathways in humans or to increase the efficacy of drugs by metabolic activation. 13)Steroidal alkaloids have been investigated in metabolism studies due to their interesting biological activities.14) Tomatidine is a known spirosolane-type Solanum alkaloid related to rubijervine.15) Incubation of tomatidine with Nocardia restrictus, Mycobacterium phlei, and Gymnoascus reesii resulted in the metabolism of tomatidine to 1,4-tomatidien-3-one, tomatidone, tomatanin-3a-ol, 1-tomatiden-3-one, and 4-tomatiden-3-one but failed to induce any N-containing side chain modification.15) Solanidine (12-deoxyrubijervine) was the subject of a previous microbial metabolism study which enabled its conversion into 11a-hydroxysolanidine using the fungus Helicostylum piriforme ATCC 8992.16) The microbes Nocardia species ATCC 21145 and Cunninghamella elegans ATCC 9245 were able to metabolize rings A and B of the Cnor-D-homosteroidal Veratrum alkaloids veratramine and jervine, respectively, but failed to metabolize rings C and D or its N-containing side chain.17,18) Rubijervine (1) was chosen for a microbial bioconversion study in an attempt to prepare new analogues, to determine if there was any metabolism in the N-containing side chain, and to compare its metabolism with that of solanidine, tomatidine, veratramine, and jervine.Twenty-three growing cultures were screened for their ability to bioconvert 1. Only one culture (C. echinulata ATCC 9244) was observed to transform 1 completely to metabolites of greater polarity. Hence this microbe was chosen for preparative-scale fermentation be...

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Section: Methodsmentioning

confidence: 99%

“…11,12) Metabolism studies have been used successfully as model systems to predict metabolic pathways in humans or to increase the efficacy of drugs by metabolic activation. 13) Steroidal alkaloids have been investigated in metabolism studies due to their interesting biological activities.…”

mentioning

confidence: 99%

Microbial Transformation of Rubijervine.

Sayed

Dunbar

2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Traditionally, drug metabolism studies were conducted on small animal models, perfused organs, tissue culture, microsomal preparation [5,6] in vitro enzyme systems and in vitro cell cultures. Microbial model was developed as one of the in vitro model to overcome the disadvantages of other models.…”

Section: Introductionmentioning

confidence: 99%

Microbial Metabolism and Inhibition Studies of Phenobarbital

Kavitha¹,

Vidyavathi²,

Asha³

et al. 2012

Trop. J. Pharm Res

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“…The use of microbial systems for the in vitro investigation of drug metabolism has been extensively reviewed (Smith and Rosazza 1983 ;Clark et al 1985) since it was first demonstrated that micro-organisms were capable of a wide range of metabolic biotransformations which closely parallel mammalian phase I metabolism (Smith and Rosazza 1975). The use of micro-organisms overcomes many of the difficulties associated with using mammalian systems in vivo and in vitro (Clark et al 1985).…”

Section: Introductionmentioning

confidence: 99%

“…The use of micro-organisms overcomes many of the difficulties associated with using mammalian systems in vivo and in vitro (Clark et al 1985). The isolation of a fungus, Verticillium lecanii, which is capable of mediating the chiral inversion of the non-steroidal anti-inflammatory drug, ibuprofen, and 2-phenylpropionic acid (2-PPA), a model substrate (Hutt et al 1993 ;Hanlon et al 1994) has previously been reported.…”

Section: Introductionmentioning

confidence: 99%

The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii

Thomason

Rhys‐Williams

Lloyd

et al. 1998

Journal of Applied Microbiology

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The fungus Verticillium lecanii has previously been shown to be capable of inverting the chirality of ibuprofen and 2-phenylpropionic acid from the (R)-enantiomer to the corresponding (S)-antipode, a phenomenon also observed in mammalian systems including man. An investigation is reported here into the substrate specificity of the enzyme system present in V. lecanii using the following 2-arylpropionic acids : ibuprofen, ketoprofen, indoprofen, suprofen, flurbiprofen and fenoprofen, together with the structurally related compounds 2-phenylbutyric acid, 2-phenoxypropionic acid, mandelic acid, atrolactic acid, etodolac and amethoxyphenylpropionic acid. The results demonstrated that V. lecanii is capable of inverting the chirality of all the 2-arylpropionic acids investigated. All were inverted in the (R) to (S) direction with the exception of ketoprofen, where inversion was observed in the reverse direction. Using the structurally related compounds as substrates, the size of the alkyl substituent at the a-carbon at the methyl group, and the presence of the methyl group at the chiral centre, were found to be critical. These results suggest that V. lecanii could be used as a basis for the production of pure enantiomers of the 2-arylpropionic acids in commercial biotransformations.

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The use of microorganisms for the study of drug metabolism

Cited by 96 publications

References 66 publications

Microbial Transformation of Rubijervine.

Microbial Transformation of Rubijervine.

Microbial Metabolism and Inhibition Studies of Phenobarbital

The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii

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