Affiliations: Malaghan Institute of Medical Research, Wellington,
New Zealand
Note: [] Address for correspondence: Dr. Michael V. Berridge, Malaghan
Institute of Medical Research, PO Box 7060, Wellington 6242, New Zealand. Tel.:
+64 4 499 6914 x 825; Fax: +64 4 499 6915; E-mail: mberridge@malaghan.org.nz
Abstract: Cytotoxicity of quinones has been attributed to free radical
generation and to arylation of cellular nucleophiles. For redox-cycling
quinones, cell injury is associated with mitochondrial permeability transition,
whereas arylating quinones directly depolarise the mitochondrial membrane and
deplete ATP. Like mitochondrial electron transport, plasma membrane electron
transport (PMET), plays a multifaceted role in cellular redox homeostasis but
the effects of quinones on PMET are unknown. Here we investigate the effects of
redox-cycling 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), arylating
1,4-benzoquinone (BQ) and mixed mechanism 2-methyl-1,4-naphthoquinone (MNQ) on
PMET, viability and growth of P815 mouse mastocytoma cells. BQ and MNQ rapidly
and extensively inhibited PMET as determined by WST-1/mPMS reduction
(IC_{50} 3.5–5 μM at 30 min) whereas
the effects of DMNQ were less pronounced. In contrast, MTT reduction (cytosolic
NADH dehydrogenase activity over 30 min) was weakly inhibited by BQ
(IC_{50} 20 μM) but not by MNQ or DMNQ
and cell viability was unaffected. Inhibition of WST-1/mPMS reduction by BQ and
MNQ but not DMNQ was fully reversed by NAC. Treatment with DMNQ, MNQ and to a
lesser extent BQ inhibited cell proliferation as determined by MTT reduction at
48 h. The effects of BQ and MNQ were reversed by NAC through covalent bonding
to BQ and MNQ, but not DMNQ. These results show that arylating quinones are
more potent inhibitors of PMET than pure redox-cycling quinones, but that
redox-cycling quinones are more cytotoxic.
Keywords: Quinone, cytotoxicity, plasma membrane electron transport, redox-cycling, arylation
DOI: 10.3233/BIO-2009-1071
Journal: BioFactors, vol. 34, no. 3, pp. 183-190, 2009
