Aflatoxin B1-adduct formation in rat and human small bowel enterocytes.
OBJECTIVE
Hepatic CYP3A enzymes have been implicated in the bioactivation of aflatoxin B1 (AFB1) to DNA binding metabolites. CYP3A enzymes are also abundant in the small bowel, and we therefore examined the ability of this tissue to form intracellular AFB1 adducts.


METHODS
Immunohistochemistry using a antibody to the stable AFB1-DNA adduct was performed on small bowel sections obtained from rats orally gavaged with AFB1 and on human small bowel biopsy specimens maintained in explant culture. 3H-AFB1 was instilled into a loop of small bowel of untreated rats and rats pretreated with the CYP3A inducer dexamethasone during vivisection. DNA was isolated from the loop 2 hours later and assayed for specific activity.


RESULTS
In both rats and humans, AFB1-adducts were detected exclusively in mature enterocytes in a pattern similar to the distribution of CYP3A enzymes. Induction of enterocyte CYP3A in rats resulted in an increase in enterocyte immunoreactive AFB1 adducts and in a 1.8-fold increase in 3H-AFB1-nucleic acid adducts (P = 0.01).


CONCLUSIONS
Intracellular AFB1 adducts are formed in the small intestine, and this reflects, at least in part, the catalytic activity of CYP3A enzymes. Because these AFB1 adducts should ultimately pass in stool, enterocyte CYP3A may represent a regulatable barrier to dietary aflatoxins.
Kolars
J C
JC
Department of Internal Medicine, Veterans Administration Medical Center, Ann Arbor, Michigan.
Benedict
P
P
Schmiedlin-Ren
P
P
Watkins
P B
PB
D016604:Aflatoxin B1 / Q000378:metabolism*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D007527:Isoenzymes / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D018736:DNA Adducts; D007527:Isoenzymes; C072611:aflatoxin B1-DNA adduct; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1