title: Pivotal role for two electron reduction in 2,3-dimethoxy-1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone metabolism and kinetics in vivo that prevents liver redox stress.
abstract: 2,3-dimethoxy-1,4-naphthoquinone (CAS-RN 6959-96-3) (DMNQ) and 2-methyl-1,4-naphthoquinone (CAS-RN 58-27-5) (MNQ:menadione) are effective one electron redox cycling chemicals in vitro. In addition, in vitro MNQ forms a thioether conjugate with glutathione by nucleophilic attack at the third carbon. In contrast, here we demonstrate that in vivo the major metabolic route is directly to the dihydronaphthoquinone for both DMNQ and MNQ followed by conjugation to mono- and di-glucuronides and sulfate. Analysis of urine and bile showed that glutathione conjugation of MNQ was only a very minor route of metabolism. DMNQ was distributed to all tissues including the brain, and MNQ was much less widely distributed. For DMNQ tissue half-life, in particular for the heart, was considerably longer than the plasma half-life. For both DMNQ and MNQ, urine 8-oxo-7,8-dihydro-2'-deoxyguanosine and liver transcriptomic analysis failed to show any evidence of redox stress. Oxidized glutathione (GSSG) in liver increased significantly at the 10 min postdosing time point only. Metabonomic analysis 96 h after DMNQ administration indicated decreased liver glucose and increased lactate and creatine suggesting an impairment of oxidative metabolism. We conclude that in vivo DMNQ and MNQ are primarily two electron reduced to the dihydronaphthoquinones and undergo little one electron redox cycling. For DMNQ, disruption of cellular oxidative metabolism may be a primary mechanism of toxicity rather than redox stress.
authors.affiliation: Department of Investigative Preclinical Toxicology, Safety Assessment, GSK R&D Ltd., Ware, UK.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Parry
authors.forename: Amy V
authors.initials: AV
authors.lastname: Pointon
authors.forename: Ursula
authors.initials: U
authors.lastname: Lutz
authors.forename: Friederike
authors.initials: F
authors.lastname: Teichert
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Charlwood
authors.forename: Pui Hei
authors.initials: PH
authors.lastname: Chan
authors.forename: Toby J
authors.initials: TJ
authors.lastname: Athersuch
authors.forename: Emma L
authors.initials: EL
authors.lastname: Taylor
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Jinli
authors.initials: J
authors.lastname: Luo
authors.forename: Kate M
authors.initials: KM
authors.lastname: Phillips
authors.forename: Angelique
authors.initials: A
authors.lastname: Vetillard
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Lyon
authors.forename: Hector C
authors.initials: HC
authors.lastname: Keun
authors.forename: Werner K
authors.initials: WK
authors.lastname: Lutz
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Gant