Induction and peroxisomal appearance of gulonolactone oxidase upon clofibrate treatment in mouse liver.
Various antihyperlipemic peroxisome proliferators are known to be carcinogenic in rodents but not in human, other primates and guinea pig, which species lost their ability to synthesize ascorbate due to mutations in the gulonolactone oxidase gene. Ascorbate synthesis is accompanied by H2O2 production, consequently its induction can be potentially harmful; therefore, the in vivo effect of the peroxisome proliferator clofibrate was investigated on gulonolactone oxidase expression in mouse liver. Liver weights and peroxisomal protein contents were increased upon clofibrate treatment. Elevated plasma ascorbate concentrations were found in clofibrate-treated mice due to the higher microsomal gulonolactone oxidase activities. Remarkable gulonolactone oxidase activity appeared in the peroxisomal fraction upon the treatment. Increased activity of the enzyme was associated with an elevation of its mRNA level. According to the present results the evolutionary loss of gulonolactone oxidase may contribute to the explanation of the missing carcinogenic effect of peroxisome proliferators in humans.
Braun
L
L
Department of Medical Chemistry, Semmelweis University of Medicine, Budapest, Hungary.
Mile
V
V
Schaff
Z
Z
Csala
M
M
Kardon
T
T
Mandl
J
J
Bánhegyi
G
G
D000818:Animals; D001205:Ascorbic Acid / Q000096:biosynthesis / Q000097:blood; D002994:Clofibrate / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050544:L-Gulonolactone Oxidase; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology; D020675:Peroxisomes / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D013401:Sugar Alcohol Dehydrogenases / Q000096:biosynthesis*
D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D013401:Sugar Alcohol Dehydrogenases; D050544:L-Gulonolactone Oxidase; D002994:Clofibrate; D001205:Ascorbic Acid