Streptozotocin-induced diabetes modulates the metabolic activation of chemical carcinogens.
The effect of chemically-induced diabetes on the hepatic microsomal mixed-function oxidase system and the activation of chemical carcinogens was investigated in animals treated with streptozotocin (STZ). In order to distinguish between the effects of the diabetogenic chemical per se and that of the diabetic state, groups of STZ-treated animals received either nicotinamide simultaneously with STZ to prevent the onset of diabetes, or daily treatment with insulin in order to reverse the effects of diabetes. STZ-treated animals exhibited higher pentoxyresorufin O-dealkylase, ethoxy-resorufin O-deethylase, ethoxycoumarin O-deethylase, aniline p-hydroxylase and NADPH-cytochrome c reductase activities; similarly, increases were seen in cytochrome P-450 and b5 levels. All of these effects were prevented by nicotinamide and, at least partly, antagonised by insulin therapy. Treatment of animals with STZ markedly increased the activation, by liver microsomes in vitro, of Trp-P-1 and Trp-P-2 to mutagens, the effect being totally preventable by nicotinamide and successfully antagonised with insulin therapy. The diabetic animals were similarly more efficient in activating MeIQ but the effect was not preventable by nicotinamide or reversed by insulin. In contrast no changes were seen in the activation of IQ and only a modest increase in the case of MeIQx. It is concluded that diabetes may modulate the metabolic activation of some chemical carcinogens, presumably by changing the ratio of the various cytochrome P-450 isoenzymes.
Ioannides
C
C
Department of Biochemistry, University of Surrey, Guildford, U.K.
Bass
S L
SL
Ayrton
A D
AD
Trinick
J
J
Walker
R
R
Flatt
P R
PR
D000818:Animals; D001711:Biotransformation; D002243:Carbolines / Q000493:pharmacokinetics; D002273:Carcinogens / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology*; D004591:Electrophoresis, Polyacrylamide Gel; D007328:Insulin / Q000627:therapeutic use; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D008970:Molecular Weight; D009152:Mutagenicity Tests; D009153:Mutagens; D009536:Niacinamide / Q000494:pharmacology; D011804:Quinolines / Q000493:pharmacokinetics; D011810:Quinoxalines / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains
D002243:Carbolines; D002273:Carcinogens; D007328:Insulin; D007527:Isoenzymes; D009153:Mutagens; D011804:Quinolines; D011810:Quinoxalines; D009536:Niacinamide; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole