Biomedical subjects
Publications and source records attributed to W G Pyerin.
Arylhydrocarbons are inducers of monooxygenase activity in epithelial cells in culture (Hela) whereas diterpene esters are not. This is one more example of a specific biochemical difference - here in gene activation - exhibited by tumor initiators and tumor promoters of the classes of compounds assayed.
Initiation of dermal melanocytes by 7,12-dimethylbenz[a]-anthracene (DMBA) in the dorsal skin of Syrian golden hamsters was investigated for its sensitivity to inhibition by 7,8-benzoflavone (BF). Initiation was carried out by a single intragastric application of DMBA (50 mg/kg body weight) and melanoma development pursued with or without subsequent promotion through repeated topical administration of 12-O-tetradecanoylphorbol-13-acetate (40 nmol/animal, 3 X weekly). A single intragastric application of BF (200 mg/kg body weight) 2 h prior to DMBA resulted in a suppression of melanoma yields by approximately 70%. Further, there were indications that BF generally causes a decrease of melanoma rates and an increase of survival rates. The study provides a first mechanistic concept for melanoma initiation by DMBA. It shows that metabolic activation of DMBA (i) is prerequisite to initiation and (ii) has a similar molecular basis as in other target cells of DMBA, the essential pathway including the cytochrome P-448-dependent monooxygenase system.
The mutagenic activities of trans-7,8-dihydro-7,8-dihydroxybenzo[a]-pyrene (BP 7,8-diol) and of trans-3,4-dihydroxy-7,12-dimethylbenz[a]-anthracene (DMBA 3,4-diol) towards S. typhimurium TA100 were measured in assays that were carried out on a micro-scale in liquid medium in the presence of microsomal fractions prepared from mouse skin or rat liver. In the presence of an NADPH-generating system, microsomal enzymes converted both diols into mutagens that were probably the respective 'bay-region' diol-epoxides. The rate of the enzyme-catalysed conversion of the BP 7,8-diol into mutagens by microsomal preparations from mouse epidermis was similar to that occurring with microsomes from rat liver. Pretreatment of mice by the topical application of benz[a]anthracene (BA) or 7,12-dimethylbenz[a]-anthracene (DMBA) increased the mutagenic activity of BP 7,8-diol mediated by mouse skin microsomal preparations by 2-fold and this was paralleled by a 4-fold increase in epidermal aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) activity. The results are discussed in relation to the high susceptibility of mouse skin to polycyclic aromatic hydrocarbon (PAH) carcinogenesis.
In order to clarify further the relation between extent of arylhydrocarbon monooxygenase (AHM) induction and tumour initiation by polycyclic aromatic hydrocarbons, AHM activity and concentration of 7,12-dimethyl-benz[alpha]anthracene (DMBA) equivalents in dorsal epidermis were determined after both intragastric and topical administration of DMBA. Although in each case the dose applied caused comparable tumor incidences, both the extent of AHM induction and the concentration of DMBA equivalents were remarkably different: while topically applied DMBA stimulated AHM several-fold, intragastric instillation led to only a slight increase, if any. The concentration of DMBA equivalents in epidermis was about 100-fold higher after topical DMBA application than after intragastric administration. These data provide further evidence that extent of tumour initiation by DMBA and of AHM induction are not causally related; positive correlations found in certain cases appear to be fortuitous. Induction of AHM seems to be rather a function of DMBA concentration adjustment in epidermis and to indicate, if anything, elevated detoxification.
The effect was investigated of 7,8-benzoflavone (BF) on tumour initiation by 7,12-dimethylbenz[a]anthracene (DMBA) applied either intragastrically or topically. A single topical application of BF drastically decreased tumour initiation via both routes. This decrease was in both cases inversely proportional to the interval between administration of DMBA and BF. The data suggest that the decisive step of metabolic activation of DMBA is mediated by cytochrome P-448 dependent monooxygenase(s) located within the epidermis.
Explore the source record for details and available documents.
By fractionation of mouse epidermis a "microsomal" fraction may be obtained with a specific EH-activity at least 6-7 times higher than that of epidermis homogenates. Such enrichment allows to utilize the radioassay with 7--3H-styrene oxide as substrate which normally is too insensitive for organs with low levels of EH-activities. By the procedure developed the unambiguous demonstration of EH-activity in the epidermis of mouse skin is possible.