MECHANISMS OF MAMMARY CARCINOGENESIS BY HYDROCARBONS

Current data in polycyclic aromatic hydrocarbon (PAH) carcinogenesis
indicate multiple mechanisms of activation in tumor initiation. PAH
bay-region vicinal diol epoxides have been studied as ultimate carcinogenic
metabolites. Such critical intermediates as PAH radical cations, certain
esters of hydroxymethyl PAH and simple PAH arene oxides, have received less
attention. We propose further study of biological activation of PAH by
one-electron oxidation to determine the role of PAH radical cations in
carcinogenesis and to provide more evidence that one-electron oxidation may
be the selective mechanism of activation in rat mammary gland by testing
PAH (a) in which the diol-epoxide region has been blocked, but which can be
activated by one-electron oxidation and (b) which we can predict will be
active or not by one-electron oxidation. To achieve these aims we will
compare carcinogenicity by direct application in mammary glands of female
Sprague-Dawley rats of (1) 3-methylcholanthrene (MC), MC-8-F and MC-10-F,
(2) benzo[a]-pyrene (BP), 10-azabenzo[a]pyrene, BP-6F, BP-7-F, BP-8-F,
BP-9-F and BP-10-F, (3) 7, 12-dimethylbenz[a]anthracene (DMBA), DMBA-2-F,
DMBA-3-F, DMBA-5-, DMBA-8-F, DMBA-9-F, DMBA-10-F and DMBA-11-F and we will
determine if (4) 12-methylbenz[a] anthracene is noncarcinogenic or weakly
carcinogenic as is 7-methylbenz[a]anthracene and if (5) dibenzo[a,e]pyrene,
dibenzo[a,h]pyrene, dibenzo[a,i]pyrene and dibenzo[a,l]pyrene are
carcinogenic. We will also study the enzymology related to PAH
activationin mammary gland since we think peroxidase enzymes activate PAH
there and we will measure and compare the aryl hydrocarbon hydroxylase and
peroxidase acitivity in uninduced and induced rat mammary homogenates.
Finally, since MC-1-OH was weakly carcinogenic in mammary gland, we
postulate its activity as due to enzymatic or nonenyzmatic formation of the
alkylating metabolite MC-1-OCOCH3. To determine if this is the activation
mechanism for MC-1-OH, BP-6-CH2OH and BA-73-CH2OH, we plan to (1) compare
in rat mammary gland the carcinogenicity of MC-1-OH vs. MC-1-OCOCH3,
BP-6-CH2OCOCH3 and BA-7-CH2OH vs. BA-7-CH2OCOCH3; (2) discover whether
MC-1-OH, MC-2-OH, BP-6-CH2OH and BA-7-CH2OH are acetylated nonenzymatically
by [14C]acetyl-CoA and (3) evaluate the above benzylic alcohols as
substrates for rat liver and mammary tissue O-acyltransferase.