TY - JOUR
T1 - Specificity of induction of cancer protective enzymes by analogues of tert-butyl-4-hydroxyanisole (BHA)
AU - Prochaska, Hans J.
AU - Bregman, Howard S.
AU - De Long, Mary J.
AU - Talalay, Paul
N1 - Funding Information:
Acknowledgements-This work was supportedb y a Special Institutional Grant from the American Cancer Society (SIG-3). H. J. P. is a Traineeo f the NIH Medical Scientist Training Program (NIH Grant GM 07309).
PY - 1985/11/1
Y1 - 1985/11/1
N2 - Protection by 2(3)-tert-butyl-4-hydroxyanisole (BHA) and related phenols against chemical carcinogens, mutagens and other toxins has been attributed to the elevation of tissue levels of non-oxygenative detoxification enzymes. To analyze the mechanisms and specificity of these enzyme inductions, we synthesized a series of mono- and dialkyl ethers of tert-butylhydroquinone (R1O-[(CH3)3C-C6H3]-OR2) and its dimer. The abilities of these compounds to elevate the cytosolic specific activities of glutathione S-transferases (measured with 1-chloro-2,4-dinitrobenzene and l,2-dichloro-4-nitrobenzene) and of NAD(P)H: quinone reductase in liver, upper small intestine and forestomach of female CD-1 mice were evaluated. The animals were fed five daily doses of 50 gmmoles of each monomer (or 25 μmoles of each dimer). The structures of the monomers examined were: R1 = H and R2 = CH3 (I), R2 = C2 H5 (VI), R2 = (CH2)2CH3 (VIII), R2 = CH1(CH3)2 (X); R1 = CH3 and R2 = C2H5 (VII), R2 = (CH2) 2CH3 (IX), R2 = CH(CH3)2 (XI); R2 = CH3 and R1 = C2H5 (III), R1 = (CH2)2 CH3 (IV) and R1 = CH(CH3)2 (V). In addition, the monomethyl (XIII), monoethyl (XIV) and mono-n-propyl (XV) ethers of BHA dimer (XII; 2,2'-dihydroxy-3,3'-di-tert-butyl-5,5'-dimethoxybiphenyl) were also prepared. Under the conditions tested, all compounds were ineffective as enzyme inducers in the forestomach but produced coordinate induction of enzymes (generally 2- to 6-fold) in the cytosols of liver and mucosa of proximal small intestine. Increases in bulk of R1 and R2 beyond methyl groups tended to decrease the inductive potency of both monomers and dimers. The lack of strict structural specificity suggests that the induction depends on metabolic conversion of the analogues to common types of metabolites.
AB - Protection by 2(3)-tert-butyl-4-hydroxyanisole (BHA) and related phenols against chemical carcinogens, mutagens and other toxins has been attributed to the elevation of tissue levels of non-oxygenative detoxification enzymes. To analyze the mechanisms and specificity of these enzyme inductions, we synthesized a series of mono- and dialkyl ethers of tert-butylhydroquinone (R1O-[(CH3)3C-C6H3]-OR2) and its dimer. The abilities of these compounds to elevate the cytosolic specific activities of glutathione S-transferases (measured with 1-chloro-2,4-dinitrobenzene and l,2-dichloro-4-nitrobenzene) and of NAD(P)H: quinone reductase in liver, upper small intestine and forestomach of female CD-1 mice were evaluated. The animals were fed five daily doses of 50 gmmoles of each monomer (or 25 μmoles of each dimer). The structures of the monomers examined were: R1 = H and R2 = CH3 (I), R2 = C2 H5 (VI), R2 = (CH2)2CH3 (VIII), R2 = CH1(CH3)2 (X); R1 = CH3 and R2 = C2H5 (VII), R2 = (CH2) 2CH3 (IX), R2 = CH(CH3)2 (XI); R2 = CH3 and R1 = C2H5 (III), R1 = (CH2)2 CH3 (IV) and R1 = CH(CH3)2 (V). In addition, the monomethyl (XIII), monoethyl (XIV) and mono-n-propyl (XV) ethers of BHA dimer (XII; 2,2'-dihydroxy-3,3'-di-tert-butyl-5,5'-dimethoxybiphenyl) were also prepared. Under the conditions tested, all compounds were ineffective as enzyme inducers in the forestomach but produced coordinate induction of enzymes (generally 2- to 6-fold) in the cytosols of liver and mucosa of proximal small intestine. Increases in bulk of R1 and R2 beyond methyl groups tended to decrease the inductive potency of both monomers and dimers. The lack of strict structural specificity suggests that the induction depends on metabolic conversion of the analogues to common types of metabolites.
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U2 - 10.1016/0006-2952(85)90443-5
DO - 10.1016/0006-2952(85)90443-5
M3 - Article
C2 - 4062966
AN - SCOPUS:0022361083
SN - 0006-2952
VL - 34
SP - 3909
EP - 3914
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 21
ER -