AROMATIC-INDUCED PREVENTION OF FATAL TOXICITY OF 7,12-DIMETHYLBENZ[a]ANTHRACENE

Abstract

Large doses of 7,12-dimethylbenz[a]anthracene (7,12-DMBA) caused the death of rats within 1 day. A small amount of any of 5 polynuclear aromatic hydrocarbons or of an aromatic amine given before the highly toxic dose of 7,12-DMBA resulted in survival for more than 2 months and the specific atrophy of testis which follows 7,12-DMBA was largely prevented. Among the protective aromatics is 7,12-DMBA itself; a small dose of 7,12-DMBA given in advance induced protection of life against an otherwise lethal dose of 7,12-DMBA but only in a proportion of the animals, and testis was not protected from injury. The highly efficient inducers of protection were condensed aromatics composed of 4 or 5 rings. Protection of life against toxicity of big doses of 7,12-DMBA by pretreatment with small doses of aromatics required time (ca. 5 to 8 hours) for its induction. Ethionine given a few minutes after a highly efficient inducer of protection, 3-methylcholanthrene (3-MC), abolished induction of protection; ethionine given 8 hours after 3-MC exerted no influence on its protective effect. A lethal dose of 7,12-DMBA resulted in a considerable reduction in incorporation of tritium in DNA from tritiated thymidine while at the same time synthesis of menadione reductase was induced in liver. A small dose of 3-MC given prior to 7,12-DMBA was advantageous in partially protecting DNA synthesis.

The diverse functionality of NQO1 and its roles in redox control

“…NQO1 knockout animals also do not have bleeding problems [ 12 ] and vitamin K protects against warfarin poisoning in both NQO1-deficient and wild type animals [ 13 ]. One of the significant and enduring early findings on NQO1 related to its inducibility by a wide variety of compounds and the ability of many of these compounds to protect against cancer [ 10 , [14] , [15] , [16] , [17] , [18] , [19] ]. This led to the emergence of the role of NQO1 primarily as a chemoprotective enzyme but as work over the years has shown, there are significant exceptions particularly with respect to anticancer compounds [ [20] , [21] , [22] , [23] , [24] ].…”

Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants

“…In the early 1960s, Charles Huggins found that pretreatment with small doses of 7,12-dimethylbenz[ a ]anthracene, other polycyclic aromatic hydrocarbons, or of aromatic amines protects against the toxicity and carcinogenicity of a high dose of the same damaging agent [10] , [11] . In the 1970s, Lee Wattenberg showed that similar protection can be achieved by dietary constituents, including phytochemicals such as indole-3-carbinol, a compound present in cruciferous vegetables, as well as phenolic antioxidants, such as 2(3)- tert -butyl-4-hydroxyanisole (BHA), a commonly added preservative in processed food [12] .…”

Rapid Detection of Inducers of Enzymes That Protect Against Carcinogens

“…Our food contains not only numerous mutagens and carcinogens but also a variety of chemicals that block carcinogenesis in animal models (4)(5)(6)(7)(8)(9)(10)(11). Furthermore, carcinogens can even protect against their own toxic and neoplastic effects or those of other carcinogens-i.e., carcinogens may act as anticarcinogens (12)(13)(14). Clearly, dietary modifications modulate cancer risk in various ways: for instance, through changes in caloric intake, by altering the consumption of nutritive and nonnutritive major components, and by providing exposure to numerous minor chemicals that may be genotoxic or protective (4-7, 9-11, 15-19).…”