INTERACTION WITH THE AROMATIC HYDROCARBON RECEPTOR, CYP1A INDUCTION, AND MUTAGENICITY OF A SERIES OF DIAMINOTOLUENES - IMPLICATIONS FOR THEIR CARCINOGENICITY
Yl. Cheung et al., INTERACTION WITH THE AROMATIC HYDROCARBON RECEPTOR, CYP1A INDUCTION, AND MUTAGENICITY OF A SERIES OF DIAMINOTOLUENES - IMPLICATIONS FOR THEIR CARCINOGENICITY, Toxicology and applied pharmacology, 139(1), 1996, pp. 203-211
The present study was undertaken to provide a rationale for the marked
difference in carcinogenic potential among isomeric diaminotoluenes,
in relation to their ability to induce their own bioactivation through
CYP1A induction, their genotoxic potential, and their ability to bind
to the cytosolic aromatic hydrocarbon (Ah) receptor, Of the four poss
ible diaminotoluenes only the 2,3- and, to a lesser extent, the 2,4-is
omer induced CYP1A activity, Similarly, only these two isomers could d
isplace [H-3]T-CDD from the hepatic cytosolic Ah receptor, In the pres
ence of Aroclor 1254-induced microsomes, 2,4- and 2,6-diaminotoluene w
ere potent mutagens in the Ames test. Only 2,4-diaminotoluene could au
toinduce its activation. Of the four isomers only 2,4-diaminotoluene i
s an established carcinogen and this is compatible with the present ob
servations that it is the only isomer that stimulates its own activati
on through CYP1A induction, is metabolically converted to genotoxic in
termediates, and binds to the Ah receptor, 2,6-Diaminotoluene is recog
nized as a mutagenic noncarcinogen and in the present studies it elici
ted a positive mutagenic response in the Ames test but failed to induc
e CYP1A activity and its own activation, and could not bind to the Ah
receptor even at concentrations as high as 5 x 10(-4) M. The present f
indings demonstrate that in vitro studies are very useful tools in pre
dicting the carcinogenic potency of isomeric chemicals. (C) 1996 Acade
mic Press, Inc.