Contribution of serum protein association to discrepancy between the in vivo and in vitro UDS results for 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843).

@article{Zhao1997ContributionOS,
  title={Contribution of serum protein association to discrepancy between the in vivo and in vitro UDS results for 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843).},
  author={Z Y Zhao and Kenneth Koeplinger and G. E. Padbury and C. S. Aaron and Philip R. Harbach and J. K. Mayo and W. B. Mattes and Gordon Bundy},
  journal={Mutation research},
  year={1997},
  volume={395 2-3},
  pages={
          119-26
        }
}
U-89843 has been shown to undergo biotransformation, both in vitro and in vivo, to form U-97924 as a major primary metabolite. U-89843 was found to be positive in an in vitro UDS mutagenesis screen conducted with primary rat hepatocytes in serum-free media. In contrast to in vitro results, no evidence of genetic toxicity of U-89843 was observed in rats in the in vivo/in vitro version of the UDS test with single oral doses up to 1400 mg/kg. The negative results may be related to more robust in… Expand
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References

SHOWING 1-10 OF 11 REFERENCES
In vitro and in vivo biotransformation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-D]pyrimidine (U-89843) in the rat.
TLDR
Although significant levels of U-89843, U-97924, and U-97865 were observed in vivo in rat plasma, only a minor amount of the carboxylic acid together with larger amounts of unidentified polar metabolites were excreted in urine and feces. Expand
Bioactivation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843) to reactive intermediates that bind covalently to macromolecules and produce genotoxicity.
TLDR
Observations suggest that the positive in vitro UDS results of U-89843 are mediated by the bioactivation of the novel pyrrolo[2,3-d]pyrimidine antioxidant, leading to reactive electrophilic intermediates derived from the (hydroxymethyl)pyrrole metabolite U-97924. Expand
Detection of genotoxic carcinogens in the in vivo-in vitro hepatocyte DNA repair assay.
TLDR
The in vivo-in vitro hepatocyte DNA repair assay is valuable for the detection and study of a variety of genotoxic carcinogens. Expand
Detection of unscheduled DNA synthesis in hepatocytes isolated from rats treated with genotoxic agents: an in vivo- in vitro assay for potential carcinogens and mutagens.
TLDR
Results indicate that this assay is a potentially useful system for assessing the genotoxic and potential carcinogenic activity of chemicals in the whole animal and a linear decline in UDS during the first 24 h post-treatment followed by a slower decline from 24 to 48 h. Expand
Design and interpretation of rat liver UDS assays.
TLDR
The rat liver UDS assay proved to be a reproducible, reliable and sensitive technique for the evaluation of genotoxicity in vivo and confirmed the utility of the pragmatic approach of the current UKEMS guidelines. Expand
Determination of warfarin-human serum albumin protein binding parameters by an improved Hummel-Dreyer high-performance liquid chromatographic method using internal surface reversed-phase columns.
The Hummel-Dreyer size-exclusion high-performance liquid chromatographic method for the determination of protein binding parameters has been improved and automated by use of an internal surfaceExpand
Partial purification of cytochromes P-450 and P-448 from rat liver microsomes.
  • A. Y. Lu, W. Levin
  • Chemistry, Medicine
  • Biochemical and biophysical research communications
  • 1972
TLDR
Cytochromes P-450 and P-448 were solubilized and partially purified from rat liver microsomes and exhibited different substrate specificities for benzphetamine and 3,4-benzpyrene. Expand
Free radicals in disease processes: a compilation of cause and consequence.
  • J. Gutteridge
  • Chemistry, Medicine
  • Free radical research communications
  • 1993
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