James K. Selkirk

An epoxide is an intermediate in the microsomal metabolism of the chemical carcinogen, dibenz(a,h)anthracene.

Abstract Washed rat liver microsomes that had been heated for 5 minutes at 50°C were incubated at room temperature for 30 seconds with 3 H-dibenz(a,h)-anthracene, TPNH, MgCl 2 , and unlabeled 5,6-epoxy-dibenz(a,h)anthracene. Analysis of the incubation mixture by TLC revealed the presence of an epoxide. This epoxide was characterized by its behavior on TLC and by its conversion under acidic conditions to the corresponding phenol. The possible role of epoxides in hydrocarbon carcinogenesis is discussed.

Binding of K-region epoxides and other derivatives of benz[a]anthracene and dibenz[a,h]anthracene to DNA, RNA and proteins of transformable cells

Abstract The firm binding of benz[a]anthracene and dibenz[a,h]anthracene and their K-region epoxides, cis -dihydrodiols, and phenols to the DNA, RNA, and proteins of exponentially growing cells has been studied. In hamster embryonic cells that undergo malignant transformation, the epoxide of benz[a]anthracene was bound to all macromolecules to a much greater extent than the hydrocarbon and other derivatives. The binding to DNA reached its maximum at 3 h. In the dibenz[a,h]anthracene series, the epoxide was highly bound to RNA and protein, but only to a small extent to DNA. The extent of binding of all compounds to DNA, RNA, and proteins of transformable G23 cells was less than to hamster cels, and the binding to malignant T24 cells was very much lower. The relationship of metabolism to binding and carcinogenesis is discussed.

The metabolism of benz[a]anthracene and dibenz[a,h]anthracene and their related “K-region” epoxides, cis-dihydrodiols and phenols by hamster embryo cells

Abstract The nature of some of the metabolites present in the cell media from hamster embryo cells that had been grown in the presence of benz[a]anthracene, dibenz[a,h]anthracene and their related K-region epoxides, phenols and cis -dihydrodiols has been investigated. Small amounts of phenols, dihydrodiols and unidentified water-soluble metabolites were detected in the media from the incubations with the hydrocarbons. Benz[a]anthracene 5,6-oxide yielded mainly the related dihydrodiol, whereas dibenz-[a,h]anthracene 5,6-oxide yielded mainly the related phenol and only small amounts of the dihydrodiol. The “K-region” phenols were metabolized to a small extent and both they and the epoxides yielded unidentified water-soluble metabolites. Much of the cis -dihydrodiols were recovered unchanged from the cell media, whereas with the other substrates large proportions of the material originally added to the media were not present in the media at the end of the incubation periods. These results are discussed in relation to those obtained in an examination of the levels of binding of the substrates to the protein, DNA and RNA of the cells that had been grown in the media.

Chemical Carcinogenesis: Nature's Metabolic Mistake

The normal biochemical defense against toxic chemicals, such as polyaromatic hydrocarbons, is to attach functional groups, such as hydroxyl, glucuronic acid, glutathione, etc. that tend to make the chemicals more water-soluble and readily excretable as harmless derivatives. However, chemical carcinogens from highly reactive intermediates on the path to final detoxification. These chemically unstable compounds, once formed, can readily attack cellular macromolecules, such as DNA, RNA, and protein, and alkylation of genetic material by these substances is critically involved with malignant transformation and mutagenesis. (Accepted for publication 5 February 1982).