Chemico-Biological Interactions 123 (1999) 219–237
Effect of inducers of DT-diaphorase on the
toxicity of 2-methyl- and
2-hydroxy-1,4-naphthoquinone to rats
Rex Munday *, Barry L. Smith, Christine M. Munday
AgResearch, Ruakura Agricultural Research Centre, Pri6ate Bag
3123
, Hamilton, New Zealand
Received 24 May 1999; received in revised form 1 September 1999; accepted 12 September 1999
Abstract
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. © 1999 Elsevier Science Ireland Ltd. All rights reserved.
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* Corresponding author. Tel.: + 64-78-385-138; fax: +64-78-385-012.
E-mail address
:
mundayr@agresearch.cri.nz (R. Munday)
0009-2797/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved.
PII: S0009-2797(99)00138-6