title: Poly(ADP-ribose) polymerase-1 (PARP-1) pharmacogenetics, activity and expression analysis in cancer patients and healthy volunteers.
abstract: There is a wide inter-individual variation in PARP-1 {PAR [poly(ADP-ribose)] polymerase 1} 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 HV (healthy volunteers) and 118 CP (cancer patients) with supporting in vivo experiments. PARP activity ranged between 10 and 2600 pmol of PAR/106 cells and expression between 0.02-1.55 ng of PARP-1/μg of 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 (odds ratio), 5.22; 95% CI (confidence interval), 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. Oestrogen supplementation activated PARP in PBMCs (peripheral blood mononuclear cells) from female mice (P=0.003), but inhibited PARP-1 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, which was confirmed in mice and shown to be associated with sex hormones. Toxic response to treatment was not associated with PARP activity and/or expression.
authors: Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Newcastle upon Tyne NE2 4HH, UK.
authors: Tomasz
authors: T
authors: Zaremba
authors: Huw D
authors: HD
authors: Thomas
authors: Michael
authors: M
authors: Cole
authors: Sally A
authors: SA
authors: Coulthard
authors: Elizabeth R
authors: ER
authors: Plummer
authors: Nicola J
authors: NJ
authors: Curtin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004789:Enzyme Activation; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010597:Pharmacogenetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D012737:Sex Factors
chemical_list: D004958:Estradiol; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases