title: Chromosomal damage and micronucleus induction by MP-124, a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor: Evidence for a non-DNA-reactive mode of action.
abstract: MP-124, a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor that competes with the binding of the PARP substrate nicotinamide adenine dinucleotide (NAD), is being developed as a neuroprotective agent against acute ischemic stroke. MP-124 increased structural chromosomal aberration in CHL/IU cells, but showed negative results in the bacterial reverse mutation test, and the rat bone marrow micronucleus (MN) and the rat liver unscheduled DNA synthesis tests after the intravenous bolus injection. Thus, MP-124 did not appear to be direct-acting mutagen. Since, PARP-1 is a key enzyme in DNA repair, the effect of continuous PARP-1 inhibition by MP-124 was further examined in the rat MN test under 24-h intravenous infusion, and an increase in micronucleated immature erythrocytes (MNIE) was observed. The increase was clearly reduced by co-treatment with nicotinic acid, which resulted in increased intracellular NAD levels. This is consistent with the established activity of MP-124 as a competitive inhibitor of PARP and provides strong evidence that the DNA-damaging effect that leads to the increase in MNIE is a secondary effect of PARP-1 inhibition. This mechanism is expected to result in a threshold for the induction of MNIE by MP-124, and allows for the establishment of a safe margin of exposure for the therapeutic use of MP-124.
authors: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1 Kazusakamatari, Kisarazu, Chiba 292-0818, Japan. Electronic address: Yamamura.Eiji@md.mt-pharma.co.jp.
authors: Eiji
authors: E
authors: Yamamura
authors: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1 Kazusakamatari, Kisarazu, Chiba 292-0818, Japan.
authors: Shigeharu
authors: S
authors: Muto
authors: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1 Kazusakamatari, Kisarazu, Chiba 292-0818, Japan.
authors: Katsuya
authors: K
authors: Yamada
authors: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1 Kazusakamatari, Kisarazu, Chiba 292-0818, Japan.
authors: Yuko
authors: Y
authors: Sato
authors: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1 Kazusakamatari, Kisarazu, Chiba 292-0818, Japan.
authors: Yumiko
authors: Y
authors: Iwase
authors: Safety Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1 Kazusakamatari, Kisarazu, Chiba 292-0818, Japan.
authors: Yoshifumi
authors: Y
authors: Uno
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations / Q000139:chemically induced*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D007262:Infusions, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced* / Q000187:drug effects; D015162:Micronucleus Tests; D009152:Mutagenicity Tests / Q000379:methods; D009525:Niacin / Q000008:administration & dosage / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D014803:Vitamin B Complex / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; C560412:MP 124; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014803:Vitamin B Complex; D009525:Niacin; D011065:Poly(ADP-ribose) Polymerases
keywords: Chromosomal damage; Genotoxicity; Micronucleus induction; Mode of action; Nicotinic acid