Effect of inducers of DT-diaphorase on the toxicity of 2-methyl- and 2-hydroxy-1,4-naphthoquinone to rats.
It has previously been shown that rats pre-treated with butylated hydroxyanisole (BHA), a well-known inducer of the enzyme DT-diaphorase, are protected against the toxic effects of 2-methyl-1,4-naphthoquinone but are made more susceptible to the harmful action of 2-hydroxy-1,4-naphthoquinone. In the present experiments, the effects of BHA have been compared with those of other inducers of DT-diaphorase. Rats were dosed with BHA, butylated hydroxytoluene (BHT), ethoxyquin (EQ), dimethyl fumarate (DMF) or disulfiram (DIS) and then challenged with a toxic dose of the naphthoquinones. All the inducers protected against the haemolytic anaemia induced by 2-methyl-1,4-naphthoquinone in rats, with BHA, BHT and EQ being somewhat more effective than DMF and DIS. A similar order of activity was recorded in the relative ability of these substances to increase hepatic activities of DT-diaphorase, consistent with a role for this enzyme in facilitating conjugation and excretion of this naphthoquinone. In contrast, all the compounds increased the haemolytic activity of 2-hydroxy-1,4-naphthoquinone. DMF and DIS were significantly more effective in this regard than BHA, BHT and EQ. DMF and DIS also caused a much greater increase in levels of DT-diaphorase in the intestine, suggesting that 2-hydroxy-1,4-naphthoquinone is activated by this enzyme in the gut. BHA, BHT and EQ had no effect on the nephrotoxicity of 2-hydroxy-1,4-naphthoquinone, but the severity of the renal lesions was decreased in rats pre-treated with DMF and DIS. The results of the present experiments show that modulation of tissue levels of DT-diaphorase may not only alter the severity of naphthoquinone toxicity in vivo, but may also change the relative toxicity of these substances to different target organs.
Munday
R
R
AgResearch, Ruakura Agricultural Research Centre, Hamilton, New Zealand. mundayr@agresearch.cri.nz
Smith
B L
BL
Munday
C M
CM
D000818:Animals; D002083:Butylated Hydroxyanisole / Q000633:toxicity; D002084:Butylated Hydroxytoluene / Q000633:toxicity; D000069462:Dimethyl Fumarate; D004221:Disulfiram / Q000633:toxicity; D004790:Enzyme Induction; D005015:Ethoxyquin / Q000633:toxicity; D005260:Female; D005650:Fumarates / Q000633:toxicity; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis*; D009285:Naphthoquinones / Q000633:toxicity*; D051381:Rats; D024483:Vitamin K 3
D005650:Fumarates; D009285:Naphthoquinones; D002084:Butylated Hydroxytoluene; D002083:Butylated Hydroxyanisole; D024483:Vitamin K 3; D005015:Ethoxyquin; D016660:NAD(P)H Dehydrogenase (Quinone); D000069462:Dimethyl Fumarate; C005090:lawsone; D004221:Disulfiram