6533b83afe1ef96bd12a71e4
RESEARCH PRODUCT
Differential sensitivity of rat hepatocyte CYP isoforms to self-generated nitric oxide.
M. Pilar López-garcíaPhilippe BeauneSantiago VerniaJulio Colomasubject
Gene isoformMaleTime FactorsBlotting WesternBiophysicsNitric OxideBiochemistryDexamethasoneNitric oxideRats Sprague-Dawleychemistry.chemical_compoundP450 contentApoenzymesCytochrome P-450 Enzyme Systembeta-NaphthoflavoneStructural BiologyGeneticsmedicineAnimalsInducerOverproductionMolecular BiologyCells CulturedDrug metabolismbiologyCytochrome P450Cell BiologyCytochrome P450 inductionCell biologyRatsIsoenzymesmedicine.anatomical_structureNG-Nitroarginine Methyl EsterBiochemistrychemistryHepatocyteEnzyme Inductionbiology.proteinHepatocytesNitric Oxide SynthaseCytochrome P450 isoformRat hepatocyte cultureHoloenzymesPeroxynitriteDrug metabolismdescription
AbstractEarly loss of P450 in rat hepatocyte cultures appears directly related to nitric oxide (NO) overproduction. This study investigates the influence of endogenously generated NO (or NO-derived species) on the relative expression of cytochrome P450 (CYP) isoforms in rat hepatocytes. Our results support the view that loss of P450 holoenzyme in culture is the ultimate consequence of a NO driven process, activated during the common hepatocyte isolation procedure, that leads to an accelerated and selective degradation of specific CYP apoproteins. Under conditions in which NO and peroxynitrite formation is operative, changes in the level of specific CYP isoforms result in a significant alteration of the CYP apoprotein profile that after 24 h of culture is quite different from that found in the liver of uninduced rats. This process is reverted by the early and efficient inhibition of NO synthesis, which allows for (1) maintenance of total P450 holoenzyme content, (2) preservation of the initial constitutive CYP pattern in culture and (3) the early expression of the normal inducibility in response to model inducers.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2001-01-12 | FEBS letters |