Abstract
Oligomeric ellagitannins (nobotanins B, E, and K) were found to be potent inhibitors of poly(ADP-ribose) glycohydrolase purified from mouse mammary tumor 34I cells. Kinetic analysis revealed that the inhibition of nobotanin B (dimer) was competitive with respect to the substrate poly(ADP-ribose), whereas nobotanin E (trimer) and nobotanin K (tetramer) exhibited mixed-type inhibition. These results suggest that the dimeric structure of ellagitannin may have a functional domain that competes with poly(ADP-ribose) on the poly(ADP-ribose) glycohydrolase molecule. To determine the inhibitory effects of oligomeric ellagitannins on poly(ADP-ribose) glycohydrolase in vivo, we examined their effects on de-poly(ADP-ribosyl)ation of some chromosomal proteins in intact 34I cells that was induced by glucocorticoid treatment. Nobotanin B caused concentration-dependent inhibition of glucocorticoid-induced de-poly(ADP-ribosyl)ation of HMG 14 and 17 and histone H1 in intact 34I cells. Interestingly, this inhibition was associated with suppression of the glucocorticoid-sensitive mouse mammary tumor virus (MMTV) mRNA synthesis. In contrast, nobotanin E and K had little inhibitory effect on either de-poly(ADP-ribosyl)ation of these proteins or induction of MMTV transcription after glucocorticoid treatment. Nobotanin B but not E and K was taken into 34I cells. These results may suggest that the suppression of glucocorticoid-sensitive MMTV transcription results from in vivo inhibition of poly(ADP-ribose) glycohydrolase by nobotanin B. These results also indicate the importance of de-poly(ADP-ribosyl)ation of HMG 14 and 17 and histone H1 in regulation of transcription of the glucocorticoid-sensitive MMTV gene.
Highlights
Were found to be potent inhibitors of poly(ADP-ribose) glycohydrolase purified from mouse mammary tumor 341 cells
To determine the inhibitory effectsof oligomeric ellagitannins on poly(ADP-ribose) glycohydrolase in uiuo, we examined their effects on de-poly(ADP-ribosy1)ationof some chromosomalproteins in intac3t 41cells that was induced by glucocorticoid treatment
Interest- A potent and specific inhibitor of poly(ADP-ribose) glycoingly, this inhibition was associated with suppression hydrolase wouldbe useful for studies on the physiological of the glucocorticoid-sensitive mouse mammary tumor significance of de-poly(ADP-ribosy1)ationof chromosomal virus (MMTV) mRNAsynthesis
Summary
Materials-Chemically defined tannins were isolated from the following plants and purified as reported previously: gallotannins, tri-, tetra-, and penta-0-galloyl-~-D-glucose(produced from tannic acid) [26];ellagitannins, geraniin (Geranium thunbergii Sieg. et Zucc.) [29]; casuarictin (Casuarina strictu Ait.) [28]; tellimagrandin I and cornusiin A (Cornus officinalisSieb. et Zucc.) [29]; rugosin D (Rosa rugosa Thunb.) [27]; coriariin A Br. et Bouch) [33]; condensed tannins, (-)-epicathechin gallate (ECG)-dimer,ECG-trimer, and ECG-tetramer (Saxifraga stolonifera Meerb) [27]. The purities of these compounds were more than 94% as analyzed by NMR. The poly(ADP-ribose) obtained had a n average chainlength of. Assay of Poly(ADP-ribose) Glycohydrolase-Poly(ADP-ribose) glycohydrolase activity was assayed by measuring the decrease of radioactivity of [3H]poly(ADP-ribose),which was adsorbed to DE-8p1aper as described previously [16,17,18]. Effect of tannins and related compounds onpoly(ADP-ribose) glycohydrolasepurified from 341 cells. Dimer Cornusiin A Rugosin D Coriariin A Nobotanin B b-3.
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