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H Mukhtar

Publications and source records attributed to H Mukhtar.

At least 163 records · Page 9Linked to original sources
PubMed1990

Evidence for the involvement of singlet oxygen in the photodestruction by chloroaluminum phthalocyanine tetrasulfonate.

In recent years, choloroaluminum phthalocyanine tetrasulfonate (A1PCTS) has been shown to be a promising photosensitizer for the photodynamic therapy (PDT) of cancer. Although its mechanism of photodynamic action is not well defined, A1PCTS is going to be under clinical trials of PDT. In this study, in vitro addition of A1PCTS to a suspension of rat epidermal microsomes followed by irradiation with red light (approximately 675 nm) resulted in significant destruction of cytochrome P-450 and associated monooxygenase activities. The photodestructive effect was dependent on both the dose of A1PCTS and the duration of light exposure. Studies using various quenchers of reactive oxygen species showed that only scavengers of singlet oxygen such as histidine, 2,5-dimethylfuran, beta-carotene and sodium azide afforded substantial protection against photodestruction. Our data indicate the direct involvement of singlet oxygen in the A1PCTS-mediated photodestructive process.

Aluminum↗
PubMed1990

Inhibition of benzoyl peroxide-mediated tumor promotion in 7,12-dimethylbenz(a)anthracene-initiated skin of Sencar mice by antioxidants nordihydroguaiaretic acid and diallyl sulfide.

Benzoyl peroxide (BPO), a free radical generating compound, is widely used in topical medications prescribed for acne vulgaris and in cosmetic products. It has been shown to possess tumor-promoting activity in murine skin initiated with chemical carcinogens such as 7,12-dimethylbenz(a)anthracene (DMBA). In the present study we assessed the effect of the antioxidants nordihydroguaiaretic acid (NDGA) and diallyl sulfide (DAS) against BPO-mediated tumor promotion in murine skin. Pretreatment of Sencar mice with NDGA and DAS prior to skin application of BPO resulted in a time- and dose-dependent inhibition of epidermal ODC induction caused by BPO. Tumor initiation was achieved by a single topical application of DMBA (10 micrograms/animal) to Sencar mice. Ten days later tumor promotion was begun by twice-weekly topical application of BPO (20 mg/animal). The anticarcinogenic effects of NDGA (25 mumol/mouse) and DAS (20 mumol/mouse) were evaluated by administering these agents topically 60 min prior to each BPO application. After 26 weeks on test, the number of benign papillomas/mouse were 0.10 +/- 0.07 and 2.15 +/- 0.30 in the NDGA and DAS pretreated group of animals as compared to 4.40 +/- 1.14 in animals receiving BPO alone. After 51 weeks on test, the number of squamous cell carcinomas/mouse were 0.00 +/- 0.00, 0.35 +/- 0.10 in the NDGA and DAS pretreated group of animals as compared to 0.65 +/- 0.12 in animals receiving BPO alone. From these data we suggest that the antioxidants NDGA and DAS can abrogate the tumor-promoting effects of BPO in murine skin and that NDGA is substantially more effective than DAS in this regard.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Effect of dietary tannic acid on epidermal, lung, and forestomach polycyclic aromatic hydrocarbon metabolism and tumorigenicity in Sencar mice.

Tannic acid inhibits the mutagenicity of several polycyclic aromatic hydrocarbons (PAHs) and their bay-region diol-epoxides. Our prior studies have shown that when applied topically to Sencar mice, tannic acid caused substantial inhibition of epidermal PAH metabolism, subsequent PAH-DNA adduct formation, and PAH-induced skin tumorigenesis (H. Mukhtar et al., Cancer Res., 48:2361-2365, 1988, and references therein). In this study the effects of tannic acid supplementation in the diet (1%, w/w, in AIN-76 diet) of Sencar mice on benzo(a)pyrene (BP) metabolism and its subsequent DNA binding and tumorigenesis in lung and forestomach were evaluated. Animals receiving a tannic acid-containing diet showed diminished aryl hydrocarbon hydroxylase and 7-ethoxy-resorufin O-deethylase activities in the forestomach and lung. Elevated glutathione S-transferase and NAD(P)H:quinone reductase activities were observed in these tissues. Maximum effects occurred after 45 days of feeding. Administration of [3H]BP p.o. to animals resulted in lower covalent binding to DNA in forestomach and lung of animals receiving tannic acid-containing diet as compared to animals receiving AIN-76 control diet. Tumor induction studies in forestomach and lung revealed significant protection against BP-induced tumorigenesis in animals fed tannic acid-supplemented diet as compared to animals fed control diet. The mice fed tannic acid-supplemented diet developed 3.3 forestomach tumors/mouse compared to 5.2 tumors/mouse in animals receiving control diet. The numbers of pulmonary tumors per mouse in animals fed tannic acid-supplemented diet and control diet were 1.6 and 3.1, respectively. Topical application of 7,12-dimethylbenz(a)anthracene to animals fed tannic acid-supplemented diet did not result in significant protection against skin tumorigenesis. However, a slight delay in the onset of skin tumor formation occurred in tannic acid-fed animals when compared to animals receiving control diet. Our data suggest that dietary supplementation with tannic acid affords protection against BP-induced forestomach and lung tumorigenesis in rodents.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Inhibition of the high affinity Fc receptor (Fc gamma RI) on human monocytes by porphyrin photosensitization is highly specific and mediated by the generation of superoxide radicals.

p72 high affinity receptors (Fc gamma RI) for the Fc portion of IgG molecules on human peripheral blood monocytes mediate a variety of beneficial functions, but also have deleterious effects in certain clinical situations. In the present study, the photosensitizing porphyrins hematoporphyrin derivative and dihematoporphyrin ether (DHE), which are known to preferentially affect the cell membrane, were found to significantly inhibit binding of mouse IgG2a antibodies to the ligand binding site of Fc gamma RI on human peripheral blood monocytes and the U937 human monocytic cell line. Fc gamma RI receptors could be identified with a monoclonal antibody which recognizes an epitope distinct from the ligand binding site, indicating that photosensitization induced a structural alteration rather than loss of the receptor molecule from the cell surface. The effect of DHE and light appeared to be highly specific, since binding of monoclonal antibodies to other surface structures was not decreased. DHE plus light-induced modulation of Fc gamma RI was found to be mediated by superoxide anions, since addition of a mimic of superoxide dismutase restored both binding of mouse IgG2a to Fc gamma RI as well as human monocyte accessory cell function. These studies identify porphyrin photosensitization as a unique mechanism by which to selectively down-regulate Fc gamma RI-mediated functions.

Antibodies, Monoclonal↗
PubMed1989

Protection against chemically induced skin tumorigenesis in SENCAR mice by tannic acid.

Tannic acid, a naturally occurring dietary polyphenol, was evaluated as a possible anticarcinogen in an initiation-and-promotion skin tumorigenesis protocol. In the 2-stage tumor protocol in SENCAR mice, using DMBA, BP and MNU as the initiating agents followed by twice-weekly applications of TPA as tumor promotor, tannic acid was found to be an effective inhibitor of tumor formation whether the tumor data are considered as cumulative number of tumors, percentage of mice with tumors or tumors/mouse. After 9 weeks of TPA application, the number of tumors/mouse in the groups receiving DMBA, BP and MNU were 32.10 +/- 3.18, 3.70 +/- 0.55 and 2.00 +/- 0.53, respectively, whereas the corresponding numbers in the DMBA, BP and MNU groups receiving prior applications of tannic acid were 11.50 +/- 2.38, 0.35 +/- 0.15 and 0.35 +/- 0.13, respectively. These results suggest that tannic acid may prove useful in reducing the risk of chemically-induced skin tumorigenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Effect of topical application of clotrimazole to rats on epidermal and hepatic monooxygenase activities and cytochrome P-450.

Clotrimazole, an N-substituted imidazole, is a widely used topical agent for the treatment of superficial fungal infections. In this study, the effect of application of clotrimazole to the skin of neonatal rats on the induction response of the cytochrome P-450-dependent monooxygenase system in epidermis and liver has been examined. A single topical application of clotrimazole (10 mg/100 g) to rats resulted in a 53% increase in hepatic cytochrome P-450 content. Clotrimazole treatment also resulted in significant induction of epidermal 7-ethoxycoumarin-O-deethylase activity. Hepatic p-nitrophenol hydroxylase, an enzyme, catalyzed principally by the ethanol inducible cytochrome P-450 isozyme, was also significantly induced (58%) by topically applied clotrimazole. This enzyme activity was undetectable in epidermal microsomes. Further characterization of the cytochrome P-450 isozymes induced in liver by clotrimazole treatment was based on monoclonal antibodies (MAbs) raised against purified rat liver cytochrome P-450 isozymes induced by phenobarbital (MAb 2-66-3) and ethanol (MAb 1-98-1). Hepatic microsomes prepared from clotrimazole-treated rats showed significant immunoreactivity on Western blot with both the MAbs whereas no reactivity occurred in epidermal microsomes. Our data indicate that topical application of clotrimazole to rats results in the induction of selected cytochrome P-450 isozyme(s) in liver and epidermis which may have implications for the therapeutic use of this compound.

Administration, Topical↗
PubMed1989

Antimutagenic activity of green tea polyphenols.

For centuries green tea has been a widely consumed beverage throughout the world. It is known to contain a number of pharmacologically active compounds. In this study water extracts of green tea (WEGT) and their major constituents, green tea polyphenols (GTP), were examined for antimutagenic activity. WEGT and GTP were found to significantly inhibit the reverse mutation induced by benzo[alpha]pyrene (BP), aflatoxin B1 (AFB1), 2-aminofluorene, and methanol extracts of coal tar pitch in Salmonella typhimurium TA100 and/or TA98 in the presence of a rat-liver microsomal activation system. GTP also inhibited gene forward mutation in V79 cells treated with AFB1 and BP, and also decreased the frequency of sister-chromatid exchanges and chromosomal aberrations in V79 cells treated with AFB1. The addition of GTP during and after nitrosation of methylurea resulted in a dose-dependent inhibition of mutagenicity. Studies to define the mechanism of the antimutagenic activity of GTP suggest that it may affect carcinogen metabolism, DNA adduct formation, the interaction of ultimate carcinogen or the scavenging of free radicals.

Aflatoxin B1↗
PubMed1989

Malignant conversion of UV radiation and chemically induced mouse skin benign tumors by free-radical-generating compounds.

It is known that the free-radical-generating compound, benzoyl peroxide (BPO) enhances malignant conversion of murine skin benign papillomas into carcinomas. To further define the role of free radicals in malignant conversion, we studied the effect of various free-radical-generating compounds on the conversion of benign papillomas into carcinomas in murine skin. Papillomas were induced in Sencar mice by 7,12-dimethylbenz[a]anthracene (DMBA) initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion and in SKH-1 hairless mice by biweekly exposure to UVB radiation. After 20 and 27 weeks respectively, papilloma yield stabilized and no new tumors developed. Skin application of acetone, TPA, BPO, 2,2-azobis(2-amidino-propane) (ABP) and tert-butyl hydroperoxybenzoic acid (BPB) increased the rate of malignant conversion in both Sencar and SKH-1 mice. In general, the rate of malignant conversion was faster in UVB-induced tumors compared with DMBA-induced tumors. The relative efficacy of each agent was similar in both groups and was in the order: acetone less than TPA less than BPB less than BPO less than ABP. Our data suggest that free-radical-generating compounds may accelerate the malignant conversion of benign papillomas into carcinoma, indicating that epigenetic mechanism(s) may also be involved in this process.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Protection against polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice by green tea polyphenols.

Green tea is a popular beverage in China and Asia and has been shown to possess antipyretic, diuretic and several other pharmacological activities. The major constituents of green tea are polyphenols which have been found to possess antioxidant and antimutagenic properties. In this study green tea polyphenols (GTP) were evaluated as an anti-initiating agent against the skin tumorigenicity induced by polycyclic aromatic hydrocarbons (PAHs) in mice. In a complete skin tumorigenesis protocol using 3-methylcholanthrene the topical application of GTP to female BALB/c mice resulted in substantial protection against the onset and subsequent development of tumors. In the two-stage skin tumorigenesis protocol using 7,12-dimethylbenz[a]anthracene (DMBA) as the initiating agent followed by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate; (TPA) as tumor promoter, topical application of GTP to female SENCAR mice afforded significant protection against skin tumorigenicity. Oral feeding of GTP in drinking water to female SENCAR mice also protected against skin tumorigenesis in DMBA - TPA-treated animals. GTP when administered topically or orally significantly inhibited PAH - DNA adduct formation in epidermis after topical application of [3H]benzo[a]pyrene or [3H]DMBA. Our results suggest that GTP has substantial anti-skin-tumor-initiating activity against PAHs and could prove useful in protecting against some forms of human cancer.

Animals↗
PubMed1989

Evidence for the metabolism of tumor promoter organic hydroperoxides into free radicals by human carcinoma skin keratinocytes: an ESR-spin trapping study.

Humans are exposed to various peroxy and hydroperoxy compounds which are in use in the cosmetic, pharmaceutical and polymer industries and which are also generated as a result of the peroxidative metabolic conversion of certain lipids. This study was designed to determine whether the organic hydroperoxides, tert-butyl hydroperoxide, cumene hydroperoxide and tert-butyl peroxybenzoate are metabolized by human carcinoma skin keratinocytes to free radicals. Incubation of keratinocytes prepared from cutaneous squamous cell carcinoma in phosphate-buffered saline (pH 7.4) containing desferrioxamine with tert-butyl hydroperoxide, cumene hydroperoxide and tert-butyl peroxybenzoate in the presence of spin trap (3,5-dibromonitrosobenzene sulfonic acid) resulted in the generation of corresponding methyl radical adducts. Prior heating of the cells to 100 degrees C abolished the generation of radical adducts. The addition of ethanol to the reaction mixture also inhibited formation of radical adducts. These data provide the first direct evidence that human carcinoma skin cells can generate free radicals from organic hydroperoxides. Since free radicals are suggested to be involved in the cascade of events occurring during tumor promotion this metabolic capacity may be an important determinant of human cancer risk for hydroperoxides.

Benzene Derivatives↗
PubMed1989

Monoclonal antibodies directed characterization of epidermal and hepatic cytochrome P-450 isozymes induced by skin application of therapeutic crude coal tar.

A single application of crude coal tar (CCT) solution (USP) to the skin of neonatal rats was shown to induce epidermal and hepatic cytochrome P-450(P-450)-dependent monooxygenase activities. To further characterize the induction response, in this study we have utilized highly specific monoclonal antibodies (MoAb) 1-7-1, 2-66-3, and 1-98-1 directed against highly purified rat liver P-450s induced by 3-methyl-cholanthrene, phenobarbital and ethanol, respectively. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of hepatic microsomes prepared from CCT-treated animals showed a significant increase in the coomassie blue stainable proteins in the P-450 region; however, this was not evident in epidermal microsomes. Immunoblot analysis of epidermal and hepatic microsomes with MoAb 1-7-1 revealed strong immunoprecipitin bands in both tissues. MoAb 2-66-3 showed significant immunoreactivity only with hepatic microsomes. Interestingly, CCT treatment resulted in suppression of immunoreactivity with MoAb 1-98-1 in hepatic microsomes. MoAb 1-7-1 and 2-66-3 exhibited concentration-dependent inhibitory effects in aryl hydrocarbon hydroxylase and 7-ethoxycoumarin-O-deethylase activities induced by CCT application. MoAb 1-7-1 was substantially more effective in this respect. Epidermal and hepatic microsomes prepared from CCT-treated rats showed significantly greater metabolism of benzo(a)pyrene (BP). MoAb 1-7-1 and MoAb 2-66-3 inhibited BP metabolism in both the tissues. However, MoAb 1-7-1 was more inhibitory in this regard as compared to MoAb 2-66-3. These studies indicate that topical application of therapeutic CCT to the skin of neonatal rats results in induction of P-450 isozyme c in epidermis and isozymes b and c in liver, and that this induction is associated with the suppression of P-450 isozyme j in liver.

Administration, Topical↗
PubMed1989

Cytochrome P-450-dependent omega-oxidation of leukotriene B4 in rodent and human epidermis.

Leukotriene B4 (LTB4,5-12-dihydroxy 6,8,10,14-eicosatetraenoic acid), an enzyme-catalyzed oxidation product of arachidonic acid, is a major inflammatory mediator. Human polymorphonuclear leukocytes and rodent hepatic microsomes catabolize LTB4 to 20-OH-LTB4 and 20-COOH-LTB4, which is mediated by a cytochrome P-450 catalyzed reaction termed the LTB4 omega-hydroxylase. In this study we investigated the catabolism of LTB4 in rat, guinea pig, and human epidermis. The incubation of 3H-LTB4 (9 microM) for 60 min in the presence of oxygen, NADPH, and epidermal microsomes prepared from neonatal fat (3.0 mg) or adult guinea pig (2.6 mg) resulted in the formation of 20-OH-LTB4 and 20-COOH-LTB4. Metabolite identification was based on co-chromatography on high pressure liquid chromatography with highly purified reference standards. The formation of 20-OH-LTB4 and 20-COOH-LTB4 was accompanied by the disappearance of LTB4. The rate of formation of 20-OH-LTB4 was 9-12-fold higher than that of 20-COOH-LTB4. Product formation was negligible with boiled microsomes, required NADPH and oxygen, was linear with respect to incubation time and protein, and was maximal at pH 7.4. LTB4-omega-hydroxylase activity was inhibited (greater than 90%) by carbon monoxide or 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF-525A) (1 mM), whereas alpha-naphthoflavone produced only moderate (13%) or no effects. Topical application of 3-methylcholanthrene and other conventional inducers of epidermal monooxygenase activities to neonatal rats (100 mg/kg, single treatment) did not result in an increase in epidermal LTB4-omega-hydroxylase activity. The addition of 3H-LTB4 (30 nmoles) to primary human keratinocytes followed by incubation at 37 degrees C resulted in time-dependent disappearance of LTB4 and appearance of 20-OH-LTB4 and 20-COOH-LTB4 in the medium. These results suggest that LTB4 is catabolized by the cytochrome P-450-dependent enzyme system in rodent and human skin and that this may participate in modulating the effects of this proinflammatory lipid in this tissue.

Animals↗
PubMed1989

Benzo(a)pyrene metabolism, DNA-binding and UV-induced repair of DNA damage in cultured skin fibroblasts from a patient with unilateral multiple basal cell carcinoma.

The metabolism of benzo(a)pyrene (BP), a ubiquitous environmental carcinogen, and its subsequent binding to DNA, and the repair of UV-induced DNA damage were studied in fibroblasts cultured from the skin of a 61-year-old male who had multiple BCC (greater than 100) on his left upper trunk. Biopsies were obtained and fibroblasts cultured from clinically normal tumour-free skin adjacent to tumour-bearing sites (TBS) and from visibly uninvolved normal skin (UNS) at distant sites. The cultured cells were incubated with [3H]-BP for 24 h and BP metabolism was assessed by HPLC and the formation of BP-diols, quinones and phenols verified. Total BP metabolism was 45% lower in TBS fibroblasts than in UNS fibroblasts. The formation of BP-7,8-diol, the precursor of the carcinogenic end product of BP metabolism, was 53% lower in TBS cells than in UNS cells. Pretreatment of UNS cells with benz(a)anthracene (BA) (x 10(-4) M) did not significantly affect BP metabolite formation whereas BA-treatment of TBS cells resulted in 55% and 76% increases in total BP metabolism and BP-7,8-diol formation, respectively. Treatment of TBS cells with BA also caused a substantial increase (95%) in BP-DNA adduct formation. Whereas DNA-binding in UNS cells was unaffected by this treatment. In response to irradiation with 2J/m2 UVC, total DNA repair was similar in both cell types; on alkaline elution it appeared that the TBS cells were more efficient in repairing UV-induced DNA strand breaks. These results suggest that BP metabolism and repair of DNA are altered in TBS cells and that patients with this type of metabolic profile may be at higher risk of the development of cutaneous neoplasms. It is also possible that fibroblasts from tumour bearing skin undergo some as yet unexplained alteration in carcinogen metabolism as a consequence of the induction of neoplasia.

Benz(a)Anthracenes↗
PubMed1989

A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization. Activation of the xanthine oxidase pathway.

Prior studies, both in vitro and in vivo, have suggested that cutaneous porphyrin photosensitization requires the generation of superoxide anion (.O2-) and various other reactive oxygen metabolites. No unifying concept has emerged, however, that unequivocally demonstrates the source of generation of these species. Since xanthine oxidase is known to generate .O2- in reperfused ischemic tissue and in certain inflammatory disorders, we attempted to assess its role in porphyrin photosensitization. C3H mice were rendered photosensitive by the intraperitoneal administration of dihematoporphyrin ether (DHE) (5 mg/kg) followed by irradiation with visible light. Murine ear swelling was used as a marker of the acute photosensitization response and involvement of oxygen radicals was evaluated using electron spin resonance (ESR) spectroscopy. The administration of allopurinol, a potent inhibitor of xanthine oxidase, afforded 90% protection against DHE-mediated acute photosensitivity in vivo. Furthermore, xanthine oxidase activity was twofold higher in the skin of photosensitized mice than in unirradiated animals. ESR spectra of 5,5-dimethyl-1-pyrroline N-oxide-trapped radicals from the skin of photosensitized mice verified the presence of .O2- and .OH, while neither of these species was detected in the skin of control mice or mice receiving allopurinol. The administration of a soybean trypsin inhibitor or verapamil before irradiation also partially blocked the photosensitivity response, suggesting that calcium-dependent proteases play a role in the activation of xanthine oxidase in this photodynamic process. These data provide in vivo evidence for the involvement of .O2- in DHE-mediated cutaneous photosensitization and suggest that these radicals are generated through the activation of the xanthine oxidase pathway. The administration of allopurinol and calcium channel blockers may thus offer new approaches for the treatment of cutaneous porphyrin photosensitization.

Allopurinol↗
PubMed1989

Hepatic microsomal metabolism of leukotriene B4 in rats: biochemical characterization, effect of inducers, and age- and sex-dependent differences.

1. The cytochrome P-450-dependent metabolism of leukotriene B4 (LTB4) by rat hepatic microsomes was characterized. Hepatic microsomes were found to metabolize LTB4 to 20-hydroxy-LTB4 and 20-carboxy:LTB4. The rate of formation of 20-hydroxy-LTB4 (14.6 pmol/min per mg protein) was 5.8-fold higher than that of 20-carboxy-LTB4 (2.5 pmol/min per mg protein). 2. LTB4 omega-hydroxylase activity required NADPH and oxygen indicating that the reaction is mediated by a mono-oxygenase system. The omega-hydroxylase activity was optimal at pH 7.4 and product formation was linear with respect to time of incubation and protein concentration. The reaction was significantly inhibited by carbon monoxide (89%), SKF 525-A (1 mM), and metyrapone (0.1 mM) whereas alpha-naphthoflavone had only marginal inhibitory effects. The apparent Km and Vmax of LTB4 omega-hydroxylase were 4 microM and 19.6 pmol/min per mg protein, respectively. 3. Ontogenic studies revealed that LTB4 omega-hydroxylase activity was low in 4-day-old rats and that there was a steady increase in enzyme activity as the animal matured. 4. Phenobarbital, 3-methylcholanthrene or Aroclor 1254 treatment of rats did not induce LTB4 omega-hydroxylase activity whereas clofibrate resulted in 61% induction in enzyme activity. No significant sex-dependent differences were observed. 5. It is concluded that hepatic metabolism of LTB4 may afford an effective mechanism for limiting many of the pro-inflammatory effects of circulating leukotrienes.

Aging↗
PubMed1989

Epidermal cytochrome P-450: immunochemical characterization of isoform induced by topical application of 3-methylcholanthrene to neonatal rat.

To further define the capacity of skin to metabolize various drugs and carcinogens by the cytochrome P-450 (P-450)-dependent monooxygenase, we studied the profile of P-450 isoform(s) in neonatal rat epidermis after application of 3-methylcholanthrene (3-MC) to skin. Highly specific monoclonal antibodies (MAbs) 2-66-3 and 1-7-1 against purified rat liver P-450 isoforms b and c induced by phenobarbital and 3-MC, respectively, were used. After a single topical application of 3-MC to rats aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin-O-deethylase and 7-ethoxyresorufin-O-deethylase activities in epidermal microsomes were induced significantly. Radioimmunoassay of epidermal microsomes from untreated control animals with 35S-labeled MAb-2-66-3 showed significant binding whereas negligible binding with MAb 1-7-1 was observed. On the other hand significant binding was observed with 35S-labeled MAb 1-7-1 with epidermal microsomes prepared from 3-MC-treated animals. Histochemical staining of epidermis from control animals showed no immunoreactivity with either MAb 1-7-1 or MAb 2-66-3 whereas epidermis obtained from 3-MC-treated rats showed significant immunoreactivity with MAb 1-7-1. Western blot analysis of epidermal microsomes prepared from control animals showed no immunoreactivity with either MAb 1-7-1 or 2-66-3 whereas epidermal microsomes prepared from 3-MC-treated animals showed distinct immunoreactivity with MAb 1-7-1. MAb 2-66-3 inhibited AHH and 7-ethoxycoumarin-O-deethylase activity (40-50%) in microsomes prepared from control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1988

Exceptional activity of tannic acid among naturally occurring plant phenols in protecting against 7,12-dimethylbenz(a)anthracene-, benzo(a)pyrene-, 3-methylcholanthrene-, and N-methyl-N-nitrosourea-induced skin tumorigenesis in mice.

Our recent studies have shown that naturally occurring dietary plant phenols such as tannic acid, quercetin, myricetin, and anthraflavic acid are capable of inhibiting polycyclic aromatic hydrocarbon (PAH) metabolism and subsequent PAH-DNA adduct formation in epidermis of SENCAR mice (M. Das, et al., Cancer Res., 47: 760-766, 1987, and 47: 767-773, 1987). In this study these plant phenols were tested for their effects against PAHs and N-methyl-N-nitrosourea-induced skin tumorigenesis in mice. Each plant phenol was evaluated as a possible anticarcinogen in an initiation and promotion and a complete skin tumorigenesis protocol. In the two-stage tumor protocol in SENCAR mice using 7,12-dimethylbenz(a)anthracene, benzo(a)pyrene, and N-methyl-N-nitrosourea as the initiating agent followed by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate as tumor promoter each plant phenol afforded significant protection against skin tumorigenicity. The protective effects were verified both by prolongation of latency period and by subsequent tumor development. In the complete carcinogenesis protocol in BALB/c mice using 3-methylcholanthrene as a tumorigen the applications of each of the plant phenols 30 min prior to each PAH application afforded significant protection by delaying the onset and the subsequent development of skin tumors. Our results suggest that these plant phenols have substantial though variable potential for modifying the risk of skin tumorigenicity induced by a wide variety of chemicals and of these tannic acid was shown to have maximal chemoprotective effects.

9,10-Dimethyl-1,2-benzanthracene↗