The effects of dietary iron overload on fumonisin B1-induced cancer promotion in the rat liver.
The present study was performed to determine whether excess hepatic iron modulates the cancer-initiating and promoting properties of FB1. Thirty-eight male F344 rats were divided into four dietary treatment groups: (i) control diet (AIN, n = 8); (ii) FB1 250 mg/kg diet (FB1, n = 10); (iii) 1-2% carbonyl iron (CI, n = 10); or (iv) FB1 plus iron loading (FB1/CI, n = 10) for 5 weeks (2 x 2 factorial design). Hepatic iron concentrations in iron-loaded animals at 5 weeks were 444 +/- 56 (CI) and 479 +/- 80 micromol/g dry weight (FB1/CI) (mean +/- SEM). All the FB1-fed rats, in the presence or absence of CI, developed a toxic hepatitis with a 4-fold rise in serum alanine transaminase (ALT) levels. FB1 appeared to augment iron-induced hepatic lipid peroxidation, as measured by the generation of thiobarbituric acid reacting substances (TBARS) in liver homogenates (P < 0.0001). Morphometric analysis showed that FB1 caused a significantly greater mean +/- SEM number of 'enzyme-altered' foci and nodules per cm2 (5.34 +/- 1.42 vs. 1.50 +/- 0.52, P < 0.05), as well as a greater area (%) of liver occupied by foci and nodules (0.33 +/- 0.12% vs. 0.05 +/- 0.03%, P < 0.001), compared with FB1/CI. The addition of FB1 to dietary iron loading caused a shift in distribution of iron from hepatocytes to Kupffer cells, probably due to phagocytosis of necrotic iron-loaded hepatocytes. In conclusion, (i) FB1 appears to cause toxicity in the liver independently from effects on lipid peroxidation; (ii) FB1 has a potentiating effect on iron-induced lipid peroxidation; and (iii) dietary iron loading appears to protect against the cancer promoting properties of FB1, possibly due to a stimulatory effect of iron on hepatocyte regeneration.
Lemmer
E R
ER
MRC/UCT Liver Research Centre, University of Cape Town, South Africa. eric_lemmer@nih.gov
Gelderblom
W C
WC
Shephard
E G
EG
Abel
S
S
Seymour
B L
BL
Cruse
J P
JP
Kirsch
R E
RE
Marasas
W F
WF
Hall
P M
PM
D000818:Animals; D002264:Carboxylic Acids / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D037341:Fumonisins; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism; D019190:Iron Overload / Q000503:physiopathology*; D007527:Isoenzymes / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009929:Organ Size; D051381:Rats; D011916:Rats, Inbred F344; D015430:Weight Gain
D002264:Carboxylic Acids; D002274:Carcinogens, Environmental; D037341:Fumonisins; D007527:Isoenzymes; C056933:fumonisin B1; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496558:Gstp1 protein, rat