6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3

@article{Zhou20106methylhydroxylationOT,
  title={6-methylhydroxylation of the anti-cancer agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by flavin-containing monooxygenase 3},
  author={Shufeng Zhou and Philip Kestell and James W. Paxton},
  journal={European Journal of Drug Metabolism and Pharmacokinetics},
  year={2010},
  volume={27},
  pages={179-183}
}
SummaryThe involvement of flavin-containing monooxygenase (FMO) in the 6-methylhydroxylation of the experimental anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was investigated by use of human liver microsomes and microsomes containing cDNA-expressed FMOs. The involvement of FMO in the formation of 6-methyl hydroxylate of DMXAA, 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA) in human liver microsomes was indicated by the fact that this biotransformation was… 
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References

SHOWING 1-10 OF 16 REFERENCES
Identification of the human liver cytochrome P450 isoenzyme responsible for the 6-methylhydroxylation of the novel anticancer drug 5,6-dimethylxanthenone-4-acetic acid.
TLDR
In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) isoenzyme involved in the 6-methylhydroxylation of 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) by using a human liver library and the involvement of CYP1A2 in DMXAA metabolism by human livers was demonstrated.
Flavin-containing monooxygenase-mediated N-oxidation of the M(1)-muscarinic agonist xanomeline.
TLDR
The data and those in the literature suggest that the increased prevalence of N-oxidized metabolites of xanomeline after s.c. dosing as compared with oral dosing may be due to differences in the affinity of various FMO family members for xnomeline or to differencesIn exposure to xanmeline that these enzymes receive under different dosing regimens.
Preclinical prediction of factors influencing the elimination of 5,6-dimethylxanthenone-4-acetic acid, a new anticancer drug.
TLDR
The kinetics of DMXAA glucuronidation in vivo are likely to be linear and unaffected by the coadministration of most glucuronidated drugs, but plasmaDMXAA clearance may be decreased in patients with renal dysfunction, illustrating the utility of in vitro techniques for the prediction of potential drug interactions and other dispositional characteristics of newly developed anticancer drugs before their administration to patients.
Metabolism and elimination of 5,6-dimethylxanthenone-4-acetic acid in the isolated perfused rat liver.
TLDR
It is demonstrated that DXAA undergoes extensive acyl glucuronidation followed by biliary excretion in the isolated perfused rat liver, and its hepatic metabolism may be saturable, and DXAA seems to be more extensively metabolized than FAA.
The mammalian flavin-containing monooxygenases: molecular characterization and regulation of expression.
TLDR
The flavin-containing monooxygenase (FMO) has been characterized in several mammalian species, including human, and may play an important role in the early steps of chemical toxicity.
Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids.
TLDR
The 5,6- dimethyl and 5-methyl-6-methoxy are the most effective analogues, showing in vivo colon 38 activity comparable to that of FAA at 10-15-fold lower doses and superior activity to FAA at the respective optimal doses, and the former has been selected for detailed evaluation.
THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. I. EVIDENCE FOR ITS HEMOPROTEIN NATURE.
TLDR
The present paper gives a detailed account of the investigations on rabbit liver microsomes and crude microsomal digests, which have led to postulate the hemoprotein nature of the pigment.
Measurement of protein using bicinchoninic acid.
...
...