Mouse skin

Imidazo[l,2-c/][l,2,4]triazines 488 were prepared (78USP4096257) from the reaction of 2-imidazocarboxylic acid hydrazide 487 with orthoesters. They inhibited cyclic-AMP phosphodiesterase in the mouse skin phosphodiesterase test and had antiasthina. 

Antitumour activity has been reported for alkyltins, particularly dibutyltin. The effect in mouse skin initiation/promotion protocols showed dibutyltin inhibiting the promotion stage (Arakawa Wada,... 

Vayalil PK, Mittal A, Kara Y, Elmets CA, Katiyar SK (2004) Green tea polyphenols prevent ultraviolet light-induced oxidative damage and matrix metal-loproteinases expression in mouse skin. J Invest Dermatol 122 1480-1487... 

We synthesized H-okadaic acid chemically and demonstrated its specific binding to the particulate and cytosolic fractions of mouse skin. The specific binding of H-okadaic acid to the particulate fraction was not inhibited by TP A, lyngbyatoxin... 

We have shown that TPA-type tumor promoters, such as lyngbyatoxin A and aplysi-atoxins exert tumor promoting activities on mouse skin through different mechanisms from those of non-TPA type tumor promoters such as palytoxin, okadaic acid, and dinophysistoxin-1. 

KATiYAR s K and MUKHTAR H (1997) Inhibition of phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate-caused inflammatory responses in SENCAR mouse skin by black tea polyphenols . Carcinogenesis, 18 1911-16. 

JAVED s, MEHROTRA N K and SHUKLA Y (1998) Chemopreventive effects of black tea polyphenols in mouse skin model of carcinogenesis , Biomed Environ Sci, 11 (4), 307-13. 

Perchellet, E.M., Abney, N.L. and Perchellet, J.-P. (1988). Stimulation of hydroperoxide generation in mouse skin treated with tumor-promoting or carcinogenic agents in vivo and in vitro. Cancer Lett. 42, 169-177. 

Fig. 4 Generalized permeation profile. From left to right the data are for n-butanol permeating hairless mouse skin at 20°, 25°, and 30° C respectively. Increasing temperature raises the flux (slope) and shortens the lag time. 

For example, 7,12-dimethylbenz[a]anthracene is a particularly potent carcinogen for the mammary gland of young female Sprague-Dawley rats after oral or intravenous administration (25,26), dietary benzo[a]pyrene leads to leukemia, lung adenoma and stomach tumors in mice (27), and either of these hydrocarbons can induce hepatomas in male mice when injected on the first day of life (28). Nevertheless, the mouse skin system has proved to be particularly valuable because of the rapidity of tumor induction, the ease of detection of tumors and because the multi-stage nature of the carcinogenic process was experimentally established in this system. 

In the newborn mouse system (Table II), the (+) anti dihydrodiol epoxide is clearly more effective than benzo[ajpyrene but this is not the case in initiation-promotion studies or in complete carcinogenesis studies on mouse skin. Nevertheless, there is always... 

Tumor Initiation in Mouse Skin Metabolite Activity/Activity of BP at Same Dose... 

Tumor Initiation in Mouse Skin Metabolite Activity/Activity of BP at Same Dose Lung Adenoma Induction in Newborn Mice Metabolite Activity/Activity of BP at Same Dose ... 

BaP is metabolically activated predominantly to the 7R,8S-dihy-drodiol-9S,10R-epoxide (anti form) and to a minor extent to 7R,8S-dihydrodiol-9R,lOS-epoxide (syn form) via 7R,8S-epoxide and 7R,8R-dihydrodiol (Figure 1). Evidence for the formation of the 7S,8S-dihydrodiol and the 7S,8R-dihydrodiol-9R,10S-epoxide from the metabolism of BaP in vivo on mouse skin has been reported (5). 

It was shown that microsomal epoxide hydrolase-catalyzed trans-addition of water to BaP 9,10-epoxide occurs stereospecifically at the C-9 position (15). Since BaP is metabolized essentially to an optically pure 9R,10R-dihydrodiol (13 and L5 Table I), the 9,10-epoxide formed in BaP metabolism must have 9S,10R absolute stereochemistry (Figure 1). Similarly, the 7,8-epoxide formed in BaP metabolism is hydrated specifically at the C-8 position to form the 7R,8R-dihydrodiol (14.21). Hence the enzymatically formed 7,8-epoxide intermediate has 7R,8S absolute stereochemistry (Figure 1). Although the 7R,8R-dihydrodiol is formed almost exclusively from BaP metabolism in rat liver microsomes (Table I) and in bovine bronchial explants (25). the 7S,8S-dihydrodiol is also formed from BaP metabolism in mouse skin epidermis in vivo (5). 

In BA metabolism, the procarcinogenic BA trans-3.4-dihydrodiol (26) constitutes 1.5-4% of all the metabolites formed by rat liver microsomes (27) and a major component of the free dihydrodiols formed by mouse skin maintained in short-term organ culture (28). In this system (28). the noncarcinogenic dihydrodiols may be preferentially removed by conjugation reactions to yield water soluble products. 

The 3,4-dihydrodiol is a major component of the free dihydrodiols formed in mouse skin maintained in short-term culture (28). The optical purities of these dihydrodiols were determined by a CSP-HPLC method (43). The metabolic fates of the enantiomeric DMBA 3,4-dihydrodiols are not yet known. Studies in our laboratory indicate that the products formed in liver microsomal metabolism of DMBA 3,4-dihydrodiol bind extensively to the components of liver microsomes and the expected 1,2,3,4-tetrols of DMBA were not detected in the acetone/ethyl acetate extract of the incubation mixture (unpublished results). It is known that these products bind extensively to DNA... 

Benzo(c)phenanthrene (BcP) is exceptionally weak or inactive as a carcinogen in experimental animals (51). On the other hand, the bay region anti diol epoxide of BcP (14) exhibits high tumor initiating activity on mouse skin (65). 

Benzo(b)-, benzo(k)-, and benzo(j)fluoranthene are common environmental contaminants (38). The tumor-initiating activity of benzo-(b)fluoranthene on mouse skin is about equal to that of DBA (38). All three isomers are mutagenic in the Ames assay (110). Syntheses of the 1,2-, 9,10-, and 11,12-dihydrodiols of benzo(b)fluoranthene by Method I have been reported (111,112). 

Comparative tumorigenicity on mouse skin of 5-MeC, 5,11-dimethyl-chrysene, and 5,12-dimethylchrysene. Each compound (5 pg) was applied to mouse skin 3 times weekly for 50 weeks. 

Methylphenanthrene fulfills the structural requirements but, as in the case of the other monomethylphenanthracenes, is inactive as a tumor initiator on mouse skin ( 5). This seems to be due to facile metabolic detoxification by formation of the 9,10-dihydrodiol, a process which is blocked in the tumorigenic isomers 1,4- and 4,10-dime thy lphenanthrene ( 5,j>). Among the methylated benzoicIphenan-threnes, the 3-,4-,5-, and 6-methyl isomers are the most tumori-genic The 1-methyl isomer, in which the methyl group is present in a 4-sided "fjord , is only weakly active like the parent hydrocarbon (23). 

Experiments on the metabolic activation of 5-MeC in mouse skin are in agreement with the pivotal role of anti-DE-I in expressing its tumorigenicity. The major DNA adduct formed in mouse skin treated with pH]5-MeC has the structure indicated in Figure 5, resulting from addition of the exocyclic amino group of deoxyguanosine to car-... 

Table II. Tumor Initiating Activity of 5-MeC Metabolites on Mouse Skin...

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