Fluorescence spectral studies on the metabolic activation of 3‐methylcholanthrene and 7,12‐dimethylbenz[a]anthracene in mouse skin

Vigny, Paul; Duquesne, M.; Coulomb, Hélène; Tierney, Brian; Grover, Philip L.; Sims, P.

doi:10.1016/0014-5793(77)80602-9

“…It should be mentioned that other metabolites of BP can also bind to DNA, especially under in vitro conditions; however, in target tissues for BP-induced neoplasia, BPDEI and BPDEII are the predominantly characterized adducts (41). Studies have also shown that other PAH, such as 7-methylbenzanthracene (42,43), benzanthracene (44,45), chrysene (46,47), and 5-methylchrysene (48), dibenzanthracene (49), 3-methylcholanthrene (3-MC) (50,51), and dimethylbenzanthracene (DMBA) (51-55) are also converted to very reactive diol epoxides like BPDEI and BPDEII that bind to DNA in vivo. All of these diol epoxides have a similar structure involving an epoxide ring in the bay region and, therefore, have been termed "bay region diol-epoxides" by Jerina and Daly (56).…”

Section: Introductionmentioning

confidence: 99%

Formation and persistence of benzo(a)pyrene metabolite-DNA adducts.

Stowers¹,

Anderson²

1985

Environ Health Perspect

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Benzo(a)pyrene (BP) and other polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental pollutants and are suspected to be carcinogenic in man. The in vivo formation of BP metabolite-DNA adducts has been characterized in a variety of target and nontarget tissues of mice and rabbits. Tissues included were lung, liver, forestomach, colon, kidney, muscle, and brain. The major adduct identified in each tissue was the (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydro-BP (BPDEI)-deoxyguanosine adduct. A 7 beta, 8 alpha-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10-tetrahydro-BP (BPDEII)-deoxyguanosine adduct, a (-)-BPDEI-deoxyguanosine adduct, and an unidentified adduct were also observed. The adduct levels are unexpectedly similar in all the tissues examined from the same BP-treated animal. For example, the BPDEI-DNA adduct levels in muscle and brain of mice were approximately 50% of those in lung and liver at each oral BP dose used. We have also examined adduct levels formed in vivo in several cell types of lung and liver. Macrophages, type II cells, and Clara cells from lung and hepatocytes and nonpparenchymal cells from liver were isolated from BP-treated rabbits. BPDEI-deoxyguanosine adduct was observed in each cell type and, moreover, the levels were similar in various cell types. These and previous results strongly suggest that DNA in many human tissues is continuously damaged from known exposure of humans to BP and other PAH. Moreover, DNA adducts formed from BP are persistent in lung and brain.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…It should be mentioned that other metabolites of BP can also bind to DNA, especially under in vitro conditions; however, in target tissues for BP-induced neoplasia, BPDEI and BPDEII are the predominantly characterized adducts (41). Studies have also shown that other PAH, such as 7-methylbenzanthracene (42,43), benzanthracene (44,45), chrysene (46,47), and 5-methylchrysene (48), dibenzanthracene (49), 3-methylcholanthrene (3-MC) (50,51), and dimethylbenzanthracene (DMBA) (51)(52)(53)(54)(55) are also converted to very reactive diol epoxides like BPDEI and BPDEII that bind to DNA in vivo. All of these diol epoxides have a similar structure involving an epoxide ring in the bay region and, therefore, have been termed "bay region diol-epoxides" by Jerina and Daly (56).…”

Section: Introductionmentioning

confidence: 99%

Formation and Persistence of Benzo(a)pyrene Metabolite-DNA Adducts

Stowers¹,

Anderson²

1985

Environmental Health Perspectives

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Benzo(a)pyrene (BP) and other polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental pollutants and are suspected to be carcinogenic in man. The in vivo formation of BP metabolite-DNA adducts has been characterized in a variety of target and nontarget tissues of mice and rabbits. Tissues included were lung, liver, forestomach, colon, kidney, muscle, and brain. The major adduct identified in each tissue was the (+ )-7,B,8a-dihydroxy-9a,lOa-epoxy-7,8,9,10-tetrahydro-BP (BPDEI)-deoxyguanosine adduct. A 713,8a-dihydroxy-93,1013-epoxy-7,8,9,10-tetrahydro-BP (BPDEII)-deoxyguanosine adduct, a ( -)-BPDEI-deoxyguanosine adduct, and an unidentified adduct were also observed. The adduct levels are unexpectedly similar in all the tissues examined from the same BP-treated animal. For example, the BPDEI-DNA adduct levels in muscle and brain of mice were approximately 50%o of those in lung and liver at each oral BP dose used. We have also examined adduct levels formed in vivo in several cell types of lung and liver. Macrophages, type II cells, and Clara cells from lung and hepatocytes and nonpparenchymal cells from liver were isolated from BP-treated rabbits. BPDEI-deoxyguanosine adduct was observed in each cell type and, moreover, the levels were similar in various cell types. These and previous results strongly suggest that DNA in many human tissues is continuously damaged from known exposure of humans to BP and other PAH. Moreover, DNA adducts formed from BP are persistent in lung and brain. The persistence of adducts in cell types that have slow turnover rates could result in significant accumulation of adducts from long-term exposure to low levels of BP. BPDEI-DNA adducts and other bulky adducts are known to inhibit replication and transcription in in vitro systems. Even if environmental exposure to PAH is too low to induce neoplasia, the accumulation of DNA adducts may produce aberrations in transcripts of genetic information in various cells and lead to other toxic effects. Thus, further elucidation of the mechanism by which BP(PAH) metabolites bind to DNA of specific cell types and of the cellselective repair of the adducts should enhance our understanding of the potential health risk from exposure to this class of environmental pollutants.

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“…The hydrodiols are different from those formed by liver microsomes, suggesting a different metabolic route. The 7-methylbenz[a]anthracene (7-MBA) metabolite is further metabolised to several dihydrodiols (VIGNY et al 1977) of which the 3,4-dihydrodiol has the highest tumour-promoting activity (CHOUROULINHOV et al 1977) in the mouse. Generally, relative to liver, AHH activity in the skin is considered low.…”

Section: F Metabolismmentioning

confidence: 99%

Pharmacology of the Skin II

1989

Handbook of Experimental Pharmacology

2

0

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PrefaceThe recent interest in the pharmacology of the skin and the treatment of its diseases has come about for two reasons. The first is a realisation that many aspects of pharmacology can be studied as easily in human skin as in animal models, where they may be more relevant to human physiology and disease. Examples of this are the action of various vasoactive agents and the isolation of mediators of inflammation after UV irradiation and antigen-induced dermatitis. The second reason is the fortuitous realisation that a pharmacological approach to the treatment of skin disease need not always await the full elucidation of aetiology and mechanism. For example, whilst the argument continued unresolved as to whether the pilo-sebaceous infection which constitutes acne was due to a blocked duct or to a simple increase in sebum production, 13-cis retinoic acid, was found quite by chance totally to ablate the disease; again, whilst cyclosporin, fresh from its triumphs in organ transplantation, has been found able to suppress the rash of psoriasis, it has resuscitated the debate on aetiology.We are therefore entering a new era in which the pharmacology and clinical pharmacology of skin are being studied as a fascinating new way of exploring questions of human physiology and pharmacology as well as for the development and study of new drugs, use of which will improve disease control and at the same time help to define pathological mechanisms.It was because of this burgeoning interest in pharmacology of skin and its diseases, that this book came about. Indeed it is long overdue and was planned several years ago; we console ourselves with the thought that the delay may have served to help define certain principles which were then only just emerging.The book is divided into two volumes which are independent but complementary; the first being an account of the general pharmacology of skin, the second volume being more concerned with disease and drugs. The first volume is divided into two parts, the one dealing with the pharmacology of skin systems and their control and the other with autocoids in normal and inflamed skin. This second volume has three parts; the first part deals with the methods of measurement which are becoming of increasing importance both in studying the pharmacological effects of drugs and the clinical pharmacology of skin; the second deals with toxicology in its widest sense -including metabolism and percutaneous absorption; and the third is an account both of specific drugs and the drugs used for specific diseases.

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Fluorescence spectral studies on the metabolic activation of 3‐methylcholanthrene and 7,12‐dimethylbenz[a]anthracene in mouse skin

Cited by 63 publications

References 15 publications

Formation and persistence of benzo(a)pyrene metabolite-DNA adducts.

Formation and persistence of benzo(a)pyrene metabolite-DNA adducts.

Formation and Persistence of Benzo(a)pyrene Metabolite-DNA Adducts

Pharmacology of the Skin II

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