Biotransformation of aflatoxin B1 in rabbit lung and liver microsomes.
Aflatoxin B1 (AFB1) is a potent hepatotoxic and hepatocarcinogenic mycotoxin that requires bioactivation to AFB1-2,3-oxide for activity. In addition to epoxidation, microsomal monooxygenases biotransform AFB1 to the less toxic metabolites, aflatoxin M1 (AFM1) and aflatoxin Q1 (AFQ1). The lung is at risk from AFB1 both via inhalation and via the circulation. In the present study, we have characterized rabbit lung and liver microsomal AFB1-DNA binding (an index of AFB1-2,3-oxide formation), AFM1 formation and AFQ1 formation. Vmax values for AFB1-DNA binding were not different between lung and liver when expressed per mg microsomal protein (1.06 +/- 0.13 and 2.12 +/- 1.30 nmol/mg/h for lung and liver respectively), but lung values were greater than liver when expressed per nmol cytochrome P450 (3.64 +/- 0.31 and 1.29 +/- 0.70 nmol/nmol P450/h for lung and liver respectively). Km values for this reaction were not different between lung and liver. Vmax values for AFM1 formation in liver microsomes were greater than in lung when expressed per mg protein, but not when expressed per nmol P450. No differences were detected for the Km for AFM1 formation between lung and liver microsomes. For AFQ1 formation, no differences were detected between Vmax values of lung and liver, regardless of whether results were expressed per mg protein or per nmol P450, while the Km for AFQ1 formation was lower in liver. SKF-525A inhibited these reactions by 63-74% in lung microsomes and 90-96% in liver microsomes. These results indicate that the lung is capable of activating AFB1, and that rabbit lung microsomes contain high activity for this reaction. Furthermore, little AFM1 and AFQ1 are formed in lung microsomes, leading to minimal shunting of AFB1 from the activation pathway.
Daniels
J M
JM
Department of Pharmacology, Queen's University, Kingston, Ontario, Canada.
Liu
L
L
Stewart
R K
RK
Massey
T E
TE
D016604:Aflatoxin B1 / Q000031:analogs & derivatives; D016607:Aflatoxin M1; D000348:Aflatoxins / Q000096:biosynthesis / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D004247:DNA / Q000378:metabolism; D007700:Kinetics; D008168:Lung / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits
D000348:Aflatoxins; D002273:Carcinogens; D011725:Pyridines; C013109:metapyrone; C006426:aflatoxin B1-2,3-oxide; C033759:aflatoxin Q1; D009249:NADP; D016607:Aflatoxin M1; D004247:DNA; D016604:Aflatoxin B1