Metabolic activation of 4-ipomeanol by complementary DNA-expressed human cytochromes P-450: evidence for species-specific metabolism.
4-Ipomeanol is a pulmonary toxin in cattle and rodents that is metabolically activated by cytochromes P-450 (P-450s). P-450-mediated activation of 4-ipomeanol to DNA binding metabolites was evaluated using a vaccinia virus complementary DNA expression system and an in situ DNA-binding assay. Twelve human P-450s and two rodent P-450s were expressed in human hepatoma Hep G2 cells and examined for their abilities to metabolically activate this toxin. Three forms, designated CYP1A2, CYP3A3, and CYP3A4, were able to catalyze significant production of DNA-bound metabolites of 20-, 8-, and 5-fold, respectively, above binding catalyzed by Hep G2 cells infected with wild-type vaccinia virus. These enzymes, with highest activities, are not known to be expressed in human or rodent lung. CYP2F1 and CYP4B1, two enzymes that are expressed in lung, display only modest 3- and 2-fold respective increased abilities to metabolically activate 4-ipomeanol. Two human forms were inactive and seven other human forms showed activities ranging from 0.5- to 2-fold above control level. Surprisingly, rabbit complementary DNA-expressed CYP4B1 was the most active enzyme (180-fold above control) among all P-450s tested in producing DNA-binding metabolites from this mycotoxin. These studies demonstrate a species difference in 4-ipomeanol metabolism and suggest caution when attempting to extrapolate rodent data to humans.
Czerwinski
M
M
Laboratory of Molecular Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892.
McLemore
T L
TL
Philpot
R M
RM
Nhamburo
P T
PT
Korzekwa
K
K
Gelboin
H V
HV
Gonzalez
F J
FJ
D001711:Biotransformation; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D013045:Species Specificity; D013729:Terpenes / Q000378:metabolism*; D014118:Toxins, Biological / Q000378:metabolism*; D014616:Vaccinia virus / Q000201:enzymology
D013729:Terpenes; D014118:Toxins, Biological; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C001470:4-ipomeanol