Induction of Aryl Hydrocarbon Hydroxylase in Mouse Tissues From a High and Low Cancer Strain and Their F
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             Hybrids
            2

Bürki, Kurt; Liebelt, A G; Bresnick, Edward

doi:10.1093/jnci/50.2.369

Cited by 50 publications

(6 citation statements)

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“…The cytochrome P-450-dependent monooxygenase system catalyzes the aromatic and olefinic epoxidations, and epoxide hydrase catalyzes trans-dihydrodiol formation from the arene oxide. Both the monooxygenase and epoxide hydrase are found in the endoplasmic reticulum of a variety of mammalian cells, including those of mouse epidermis (26,27). Therefore, under the experimental conditions of this study, dihydrodiols and diol epoxides could be formed from benz[a]anthracene in mouse skin.…”

mentioning

confidence: 81%

Tumorigenicity of five dihydrodiols of benz(a)anthracene on mouse skin: exceptional activity of benz(a)anthracene 3,4-dihydrodiol.

Wood¹,

Levin²,

Chang³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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Benz[a anthracene and the five metabolically possible vicinal trans dilydrodiols of benz[ajanthracene were tested for ability to initiate skin tumors in CD-i female mice.A single topical a fication of 0.4-2.0 ,mol of hydrocarbon was followed 18 days later by twice weekly applications of the skin promoter 12-O-tetradecanoylphorbol-13-acetate. Comparisons of latency period, percent of mice with tumors, and number of papillomas observed per mouse indicated that benz[alanthracene 3,4-dihydrodiol was 10-to 20-fold more tumorigenic than the parent hydrocarbon, benz[aJanthracene. The nz[a anthracene 1,2-, 5,6-, 8,9-, and 10,11-dihydrodiols were all less active tumor initiators than was benz[aJanthracene. The high tumorigenicity of benzajanthracene 3,4dihydrodiol, presumably the result of metabolism to either or both of the diastereomeric benztalanthracene 3,4diol-1,2-epoxides, supports the bay region theory of polycyclic hydrocarbon carcinogenicity and provides the first example of a proximate carcinogenic metabolite that is much more active than the parent hydrocarbon on mouse skin.Highly active metabolic intermediates, designated ultimate carcinogens, are responsible for the carcinogenic activity of polycyclic-aromatic hydrocarbons and many other cancercausing chemicals (1-4). Benzo[a]pyrene 7,8-diol-9,10-epoxide appears to be the principal ultimate carcinogen of the polycyclic environmental pollutant benzo[a Ipyrene. This conclusion is based, in part, on DNA binding (5) and the exceptionally high mutagenicity of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides (6-8), as well as the high carcinogenicity of one of these diastereomers (9). The two proximate metabolic precursors of the 7,8-diol-9,10-epoxide, benzo[a]pyrene 7,8-oxide (10), and trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (9, 11) have the requisite high carcinogenicity.The possibility that diol epoxides are responsible for the carcinogenicity of other polycyclic aromatic hydrocarbons is a subject of substantial importance. We have developed a general hypothesis to predict which diol epoxides of polycyclic hydrocarbons are the ultimate carcinogenic forms of the parent hydrocarbon (8,12,13). This hypothesis proposes that the formation of a bay regiont epoxide on a saturated, angular benzo-ring is a principal determinant of polycyclic hydrocarbon carcinogenicity. Application of the bay region theory to benz [a]anthracene (BA) predicts that 3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenz[a]anthracene (BA 3,4-diol-1,2-epoxide) will have greater mutagenic and carcinogenic activity than other metabolically possible diol epoxides of benz [a]anthracene. Since dihydrodiol formation precedes epoxidation at the adjacent double bond, trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene (BA 3,4-dihydrodiol) would be the critical metabolic precursor of the bay region diol epoxide of benz [a]anthracene. This proposal contrasts to the suggestion of Grover, Sims, and associates that the BA 8,9-diol-10,11-epoxide should have high biological activity and that...

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mentioning

confidence: 81%

Tumorigenicity of five dihydrodiols of benz(a)anthracene on mouse skin: exceptional activity of benz(a)anthracene 3,4-dihydrodiol.

Wood¹,

Levin²,

Chang³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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“…For instance, the metabolism of 3-MC by liver (BURKI et al 1973) and of DMBA by epidermis (DIGIOVANNI et al 1980) was found to be similar when responsive or non-responsive strains of mice were compared. On the other hand an increased metabolism of hydrocarbon to its proximate or ultimate carcinogen, especially following induction, and a correlation with susceptibility to PAH in systems derived from responsive compared with non-responsive strains have been noted for BaP metabolism in liver (HOLDER et al 1975), lung (SEIFRIED et al 1977 and skin (LEGRAVEREND et al 1980;BICKERS et al 1983).…”

Section: Metabolismmentioning

confidence: 99%

“…Similar studies which have attempted to rationalise variations in sensitivity of different tissues are fewer in number. Both GELBOIN (1969) andBURKI et al (1973) measured basal and induced AHH levels in a variety of tissues of mice and other species. In all cases liver was found to contain the highest activity, while the extent of induction varied in the other tissues.…”

Section: Ll Tissue Differencesmentioning

confidence: 99%

Polycyclic Aromatic Hydrocarbons: Metabolism, Activation and Tumour Initiation

Hall¹,

Grover²

1990

Handbook of Experimental Pharmacology

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“…The level of carcinogen metabolites in the serum is known to be influenced by the potential of an animal to bioactivate the chemical. A number of studies have suggested a positive correlation between the level of carcinogen metabolizing enzymes, such as cytochrome P-450 1 A1 , and the PAH-induced tumor susceptibility of an animal [36,37]. Thus, mouse strains susceptible to PAH carcinogenicity (e.g., B6C3F1 and C57B1/6), which show a greater capacity for bioactivating carcinogens to reactive metabolites, have much higher levels of metabolizing enzymes versus resistant strains (e.g., DBA/2) [38].…”

Section: Discussionmentioning

confidence: 99%

Interception of reactive, DNA adduct‐forming metabolites present in rodent serum following carcinogen exposure: Implications for use of body fluids in biomonitoring

Garg

Beach

Gupta

1993

Teratog Carcinog Mutagen

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The detection of adduct-forming metabolites in the serum of carcinogen treated animals by 32P-postlabeling was evaluated as a novel approach to overcome the stringent requirement of obtaining DNA from tissues in human biomonitoring assessments. Benzo[a]pyrene (BP) was given i.p. to B6C3F1, C57B1/6, ICR, and DBA/2 mouse strains as well as Sprague-Dawley rats. Three adducts related to BP were detected in the liver and/or lung of Sprague-Dawley rats or B6C3F1, C57B1/6, and ICR mice; a single adduct was detected in the liver and lung of the DBA/2 mouse strain. Adducts chromatographically similar to those found in these tissues were also detected when salmon sperm DNA was incubated with the serum of BP-treated animals. Benzidine treatment induced the formation of one adduct in the liver of B6C3F1 mice, which was chromatographically similar to dG-C8-N'-acetylbenzidine. An identical adduct was detected in the salmon sperm DNA incubated with the serum of these mice. Cyclopenta[cd]pyrene treatment produced four major and three minor adducts in the liver or lung of B6C3F1 mice, all but two of which were detected in DNA incubated with serum of cyclopenta[cd]pyrene-treated animals. Large interstrain differences in the serum level of BP adduct-forming metabolites as well as tissue DNA adducts were found which correlated with previously observed strain-specific trends in sensitivity to PAH-mediated carcinogenesis. Thus, levels of BP adduct-forming metabolites were found in the following descending order: B6C3F1, C57B1/6, ICR, and DBA/2. BP-derived adduct-forming metabolites were detectable as late as 2 d and 5 d post-treatment in the serum of C57B1/6 mice or Sprague-Dawley rats, respectively, which seems to coincide well with the reported species-specific turnover of serum albumin; a protein know to be involved in the transport of reactive metabolites throughout the systemic circulation. The results obtained clearly indicate the presence of adduct-forming carcinogen metabolites in the serum of treated animals, which seemingly irrespective of their chemical nature, can be intercepted with exogenous DNA and detected by 32P-postlabeling. Successful application of a serum-based approach coupled with the use of the generally applicable, ultrasensitive 32P-postlabeling assay could evade the need for obtaining DNA from tissues, currently the major impediment in human biomonitoring studies.

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Induction of Aryl Hydrocarbon Hydroxylase in Mouse Tissues From a High and Low Cancer Strain and Their F 1 Hybrids 2

Cited by 50 publications

References 0 publications

Tumorigenicity of five dihydrodiols of benz(a)anthracene on mouse skin: exceptional activity of benz(a)anthracene 3,4-dihydrodiol.

Tumorigenicity of five dihydrodiols of benz(a)anthracene on mouse skin: exceptional activity of benz(a)anthracene 3,4-dihydrodiol.

Polycyclic Aromatic Hydrocarbons: Metabolism, Activation and Tumour Initiation

Interception of reactive, DNA adduct‐forming metabolites present in rodent serum following carcinogen exposure: Implications for use of body fluids in biomonitoring

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