Activation Of Carcinogenic Polycyclic Hydrocarbons Research Articles

Metabolism and activation of carcinogenic polycyclic hydrocarbons by human mammary cells

Summary The metabolism of two 3H-labelled hydrocarbons, benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene, into water-soluble and organic solvent-soluble metabolites, including dihydrodiols, has been examined in cultures of mammary epithelial cell aggregates from five individuals. Both hydrocarbons also became bound to the DNA and proteins of the cells. The hydrocarbon-deoxyribonucleoside adducts formed from benzo(a)pyrene closely resembled, when examined by Sephadex LH20 column chromatography, those that are formed, for example, in reactions of the related ‘bay-region’ diol-epoxide with DNA and in mouse skin, a tissue in which this hydrocarbon is carcinogenic.

Mutagenicity of metabolically activated benzo[a]anthracene 3,4-dihydrodiol: Evidence for bay region activation of carcinogenic polycyclic hydrocarbons

Benzo[a]anthracena and the 5 metabolically possible trans dihydrodiols of benzo[a]anthracene were metabolized, in the presence of S.thyphimurium strain TA100, by a highly purified hepatic microsomal monooxygenase system. The metabolic product(s) of benzo[a]anthracene 3,4-dihydrodiol was nearly 10 times as mutagenic to the bacteria as were the metabolites of benzo[a]anthracene and the other four dihydrodiols. The marked activation of benzo[a]anthracene 3,4-dihydrodiol, presumably to the 3,4-diol-1,2-epoxide is consistent with and supports the hypothesis that bay region epoxides of unsubstituted polycyclic hydrocarbons are ultimately reactive forms of these carcinogenic compounds.

Activation of carcinogenic polycyclic hydrocarbons in polyoma‐virus‐transformed cells as a prerequisite for polyoma virus induction

Polyoma-virus (PV)-transformed cell clones, which are inducible for virus synthesis by various physical and chemical agents, metabolize the chemically non-reactive carcinogen benzo(a)pyrene (BP) into water soluble products. In cultures of such clones, which metabolize BP to a level of 30-6-% of that of normal cells, up to 10.4% of the cells were induced for PV synthesis by BP, 20-methylcholanthrene (MCA) and 7,12-dimethylbenz(a)anthracene (CMBA). No PV induction was observed with the non-carcinogenic polycyclic hydrocarbons pyrene chrysene and benz(a)-anthracene. A proportion of subclones, isolated from a PV- inducible clone, which metabolized 0.1 mug or less BP per 10-6 cells were all inducible for PV synthesis by these carcinogens. Subclones isolated from an inducible clone pretreated with BP were shown to metabolize less than 0.1 mu BP per 10-6 cells and were resistant to virus induction by the carcinogenic polycyclic hydrocarbons. Benzoflavone, which inhibited the metabolism of BP in clones metabolizing high levels of this carcinogen, also prevented the induction of PV antigen and infectious virus synthesis in these clones. The data indicate a relationship between the carcinogenicity of polycyclic hydrocarbons and their ability to induce virus in the PV-transformed cells and suggest that virus induction depends on metabolic conversion of these hydrocarbons into similar reactive compounds that are responsible for malignant transformation and mutagenesis.

Possible role of 6-hydroxymethylbenzo(a)pyrene as a proximate carcinogen of benzo(a(pyrene and 6-methylbenzo(a)pyrene.

AbstractBenzo[a]pyrene (B[a]P) and 6‐methylbenzo[a]pyrene ( 6‐MeB[a]P) are metabolized by fortified rat‐liver homogenates to a number of metabolites including one which is indistinguishable from 6‐hydroxymethylbenzo[a]pyrene (6–OHMeB[a]P) by either thin‐layer chromatography or ultra‐violet absorption spectra. This compound is a potent carcinogen when administered by subcutaneous injection to rats. These observations are in accord with the hypothesis that methylation or hydroxymethylation is one of the first steps in metabolic activation of carcinogenic polycyclic hydrocarbons.

New Models of Human Disease in Syrian Hamsters

The resemblance of five new constitutional (hereditary) diseases in inbred Syrian hamsters (muscular dystrophy, cardiomyopathy with congestive heart failure, obesity, adrenal adenomatosis, and progressive hind-leg paralysis) to human disease entities makes these animals useful for systematic experimental study. The hamsters have also demonstrated peculiar inherited susceptibilities to teratogenic agents (thalidomide), poisoning by cyclamates through coronary and systemic calcinosis, and the carcinogenic activity of polycyclic hydrocarbons.

SUSCEPTIBILITY OF SYRIAN HAMSTERS TO INDUCTION OF FIBROSARCOMAS WITH A SINGLE INJECTION OF 3,4,9,10-DIBENZPYRENE.

THE carcinogenic activity of polycyclic hydrocarbons administered subcutaneously to hamsters was first described by Gye and Foulds1. Later, Halberstaedter2, Crabb3, and Lutz et al.4 reported the sarcomagenic activity of other polycyclic hydrocarbons in hamsters. These investigators were primarily interested in the question of transplantability and metastases and used multiple injections for tumour production.