Open AccessIn vivo study of the effect of antiviral acyclic nucleotide phosphonate (R)-9-[2- (phosphonomethoxy) propyl]adenine (PMPA, tenofovir) and its prodrug tenofovir disoproxil fumarate on rat microsomal cytochrome P450
Author(s) -
Eva Anzenbacherová,
Pavel Anzenbacher,
Zdeněk Zı́dek,
E. Buchar,
Eva Kmonı́čková,
Petr Potměšil,
Jaekvindová,
Alena Veinlichová,
Antonı́n Holý
Publication year - 2008
Publication title -
physiological research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.647
H-Index - 70
eISSN - 1802-9973
pISSN - 0862-8408
DOI - 10.33549/physiolres.931319
Subject(s) - microsome , cyp1a2 , cytochrome p450 , chemistry , in vivo , cyp2e1 , hydroxylation , pharmacology , prodrug , tenofovir , enzyme , biochemistry , biology , human immunodeficiency virus (hiv) , microbiology and biotechnology , immunology
The total content of rat liver microsomal cytochrome P450 (CYP)significantly decreased after repeated i.p. administration of theantiviral agent tenofovir ((R)-9-[2-(phosphonomethoxy)propyl]adenine) and tenofovir disoproxil at a daily dose 25 mg/kg,although the content of liver microsomal protein did not change.The decrease of the CYP content was accompanied byconcomitant increase of the amount of inactive CYP form,cytochrome P420. This effect was confirmed by a parallel studyof the activities of selected CYP forms, CYP2E1 (p-nitrophenolhydroxylation) and CYP1A2 (7-ethoxyresorufin deethylation). Theactivity (expressed relatively to the protein content) of both CYPforms decreased significantly following the decrease of the totalCYP. On the other hand, the CYP2E1 activity expressed relativelyto the decreasing total CYP content remained unchanged.However, CYP1A2 activity also decreased when calculatedrelatively to the total native CYP content indicating lower stabilityof this form. Semiquantitative RT-PCR showed no significantchanges in expression of major rat liver microsomal CYP formsafter tenofovir treatment. In conclusion, repeated administrationof tenofovir in higher doses led to significant decrease of therelative proportion of active liver microsomal CYPs accompaniedby a conversion of these enzymes to the inactive form (CYP420)maintaining the sum of CYP proteins unchanged.