Effect of inducers of DT-diaphorase on the haemolytic activity and nephrotoxicity of 2-amino-1,4-naphthoquinone in rats.
Reduction of naphthoquinones by DT-diaphorase is often described as a detoxification reaction. This is true for some naphthoquinone derivatives, such as alkyl and di-alkyl naphthoquinones, but the situation with other substances, such as 2-hydroxy-1,4-naphthoquinone, is more complex. In the present study, the effect of several substances that are known to increase tissue activities of DT-diaphorase on the toxicity of 2-amino-1,4-naphthoquinone has been investigated. Like 2-hydroxy-1,4-naphthoquinone, the 2-amino-derivative was found to cause both haemolytic anaemia and renal tubular necrosis in rats. Again like 2-hydroxy-1,4-naphthoquinone, the severity of the haemolysis induced by the 2-amino derivative was increased in animals pre-treated with inducers of DT-diaphorase, but the degree of nephrotoxicity was decreased. With these substances, therefore, DT-diaphorase both activates and detoxifies the quinone, depending on the target organ. It is not possible to generalize with regard to the effects of modulation of tissue levels of DT-diaphorase on naphthoquinone toxicity in vivo, since this may change not only the severity of the toxic effects, but also the target organ specificity. In evaluating the possible therapeutic applications of such compounds, the possibility of toxic effects upon the blood and kidney must be borne in mind. In man, renal damage by compounds such as 2-hydroxy- and 2-amino-1,4-naphthoquinone may be a particular problem, because of the low level of DT-diaphorase in human liver.
Munday
Rex
R
AgResearch, Ruakura Agricultural Research Centre, Private Bag 3123, Hamilton 2001, New Zealand. rex.munday@agresearch.co.nz
Smith
Barry L
BL
Munday
Christine M
CM
D000743:Anemia, Hemolytic / Q000139:chemically induced; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D000069462:Dimethyl Fumarate; D004221:Disulfiram / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005015:Ethoxyquin / Q000494:pharmacology; D005260:Female; D005650:Fumarates / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects*; D008658:Inactivation, Metabolic; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis*; D009285:Naphthoquinones / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005650:Fumarates; D009285:Naphthoquinones; D002084:Butylated Hydroxytoluene; D002083:Butylated Hydroxyanisole; D005015:Ethoxyquin; D016660:NAD(P)H Dehydrogenase (Quinone); D000069462:Dimethyl Fumarate; D004221:Disulfiram