Induction of cytochrome P4501A1 and P4504A1 activities and peroxisomal proliferation by fumonisin B1.
The effects of repeated exposure to fumonisin B1 (FB1) on hepatic and renal mixed function oxidase activities and peroxisomal proliferation has been examined in rats following intraperitoneal administration at three dose levels (0.125, 0.25, and 2.5 mg/kg) once a day for 6 days. At the two highest doses, FB1 increased the renal and hepatic N-demethylation of erythromycin (CYP3A1) and the hepatic O-deethylation of ethoxyresorufin (CYP1A1). FB1, at the highest dose of 2.5 mg/kg, also increased the renal O-deethylation of ethoxyresorufin. The liver, but not the kidney, was also susceptible to FB1-dependent induction of the 12- and 11-hydroxylation of lauric acid, suggesting induction of the CYP4A subfamily. Immunoblot studies employing solubilized microsomes from FB1-treated rats revealed that FB1, at the two highest doses, increased the apoprotein levels of CYP1A1 and CYP4A1. The same treatment with FB1 increased the beta-oxidation of palmitoyl-coenzyme A (CoA) in liver homogenates, and immunoblot analysis showed an increase in the apoprotein levels of the trans-2-enoyl-CoA hydratase trifunctional protein. The possible implications of these findings to the hepatocarcinogenicity of this mycotoxin are discussed.
Martinez-Larrañaga
M R
MR
Department of Toxicology, Faculty of Veterinary Medicine, Universidad Complutense de Madrid, Spain.
Anadón
A
A
Diaz
M J
MJ
Fernandez
R
R
Sevil
B
B
Fernandez-Cruz
M L
ML
Fernandez
M C
MC
Martinez
M A
MA
Anton
R
R
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D037341:Fumonisins; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009183:Mycotoxins / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D002274:Carcinogens, Environmental; D037341:Fumonisins; D009183:Mycotoxins; C056933:fumonisin B1; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019363:Cytochrome P-450 CYP1A1; D042926:Cytochrome P-450 CYP4A