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Poly(ADP-ribose) polymerase-1 (PARP-1) pharmacogenetics, activity and expression analysis in cancer patients and healthy volunteers
Lookup NU author(s)
Dr Sally Coulthard
Professor Ruth Plummer
Professor Nicola Curtin
Zaremba T, Thomas HD, Cole M, Coulthard SA, Plummer ER, Curtin NJ
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There is a wide inter-individual variation in PARP activity, which may have implications for health. We investigated if the variation (i) is due to polymorphisms in the PARP-1 gene or PARP-1 protein expression and (ii) affects patients' response to anticancer treatment. We studied 56 healthy volunteers (HV) and 118 cancer patients (CP), with supporting in vivo experiments. PARP activity ranged between 10-2600 pmol PAR/106 cells and expression between 0.02-1.55 ng PARP-1/µg protein. PARP-1 expression correlated with activity in HV (R2=0.19, P=0.003) and CP (R2=0.06, P=0.01). A short CA repeat in the promoter was significantly associated with increased cancer risk (OR, 5.22; 95% CI, 1.79-15.24). PARP activity was higher in men than women (P=0.04) in the HV. Male mice also had higher PARP activity than females or castrated males. Estrogen supplementation activated PARP in PBMCs from female mice (P=0.003) but inhibited PARP in their livers by 80%. PARP activity and expression were not dependent on the investigated polymorphisms but there was a modest correlation of PARP activity with expression. Studies in the HV revealed sex differences in PARP activity, confirmed in mice and associated with sex hormones. Toxic response to treatment was not associated with PARP activity and/or expression.
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