It has been demonstrated that in humans certain factors such as early menarche, late pregnancy, and nulliparity are associated with a higher risk of developing breast cancer, while early pregnancy acts as a protective factor. Induction of mammary cancer in rats by administration of the chemical carcinogen 7, 12-dimethylbenz(a)anthracene reveals that the same factors influencing human breast cancer risk also affect the susceptibility of the rat mammary gland to the chemical carcinogen. Nulliparous rats and rats undergoing pregnancy interruption are more susceptible to developing carcinomas. This fact has been attributed to the incomplete differentiation of the gland at the time of carcinogen administration. Parous rats are resistant to the carcinogenic effect of DMBA, which is explained by the complete development of the gland attained during pregnancy and lactation. This development is manifested by the differentiation of terminal end buds into secretory units, which have a smaller proliferative compartment; the epithelial cells of these secretory units have a longer cell cycle, less avidity for binding DMBA, and possess a more efficient DNA excision repair capacity.

Differentiation of the mammary gland and susceptibility to carcinogenesis

Publisher Summary This chapter deals with the microbial transformation of polycyclic aromatic hydrocarbons (PAHs) The similarities and differences between the microbial and mammalian metabolism are described Bacteria, filamentous fungi, yeasts, cyanobacteria, diatoms, and other eukaryotic algae have the enzymatic capacity to oxidize PAHs that range in size from naphthalene to benzo[ a ]pyrene The hydroxylation of PAHs always involves the incorporation of molecular oxygen; however, there are differences in the mechanism of hydroxylation of PAHs by prokaryotic and eukaryotic microorganisms Bacteria oxygenate PAHs to form a dihydrodiol with a cis configuration The genes for the initial oxidation of PAHs are localized on plasmids In contrast to bacteria, fungi oxidize PAHs via a cytochrome P-450 monooxygenase to form arene oxide, which can isomerize to phenols or undergo enzymatic hydration to yield trans-dihydrodiols Multiple oxidative pathways may be involved in the cyanobacterial metabolism of PAHs Studies on PAH metabolism are entering a new era; biochemical genetic techniques such as gene cloning and transposon mutagenesis will provide new insight into the biochemistry and regulation of PAH degradative pathways

Microbial metabolism of polycyclic aromatic hydrocarbons.

Targeted Disruption of the Microsomal Epoxide Hydrolase Gene: MICROSOMAL EPOXIDE HYDROLASE IS REQUIRED FOR THE CARCINOGENIC ACTIVITY OF 7,12-DIMETHYLBENZ[a]ANTHRACENE

3 – Involvement of Dihydrodiols and Diol Epoxides in the Metabolic Activation of Polycyclic Hydrocarbons Other than Benzo[a]pyrene

The metabolic activation of the polycyclic hydrocarbons benzo [a] pyrene and 7-methylbenz [a] anthracene in mouse skin appears to involve the formation of vicinal diol-epoxides [l] that react with nucleic acids in this tissue [2-51. This mechanism of activation may be a general one for this class of chemical carcinogens and efforts are now being made to extend the hypothesis to include other hydrocarbons. The examination, using photon-counting spectrofluorimetry, of nucleic acids isolated from tis’sues treated in vivo with polycyclic hydrocarbons, has already proved to be of value in identifying the sites of activation in benzo [a] pyrene [2] and in 7-methylbenz [a] anthracene [4,6] . In this paper we present data from fluorescence studies obtained with the potent carcinogens 3-methylcholanthrene (I) and 7,12-dimethylbenz[a] anthracene (II). These data show that the hydrocarbon moieties, bound to the DNA of mouse skin treated in vivo with either of the parent hydrocarbons, have spectral characteristics consistent with the retention of a substituted anthracene nucleus in

Brian Tierney

Papers

The formation of dihydrodiols by the chemical or enzymic oxidation of benz[a] anthracene and 7,12-dimethylbenz[a] anthracene.