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H Mukhtar

Publications and source records attributed to H Mukhtar.

At least 145 records · Page 8Linked to original sources
PubMed1992

Photodynamic effects of chloroaluminum phthalocyanine tetrasulfonate are mediated by singlet oxygen: in vivo and in vitro studies utilizing hepatic microsomes as a model membrane source.

Chloroaluminum phthalocyanine tetrasulfonate (AlPcTS) is a promising photosensitizer for the photodynamic therapy (PDT) of cancer. In this study, we investigated the in vivo and in vitro photodestruction of hepatic microsomal membranes by AlPcTS and studied the role of reactive oxygen species in this process. Irradiation of hepatic microsomes prepared from AlPcTS-pretreated SENCAR mice to approximately 675 nm light resulted in rapid destruction of cytochrome P450 and associated monooxygenase activities, and enhancement of lipid peroxidation in a light-dose-dependent manner. The specificity of AlPcTS and light dependency on photodestruction of microsomal membranes was confirmed by Western blot analysis. Similar results were obtained when AlPcTS was added in vitro to a suspension of hepatic microsomes prepared from control animals followed by irradiation to approximately 675 nm light. Among the quenchers of singlet oxygen, superoxide anion, hydrogen peroxide, and hydroxyl radical, only the quenchers of singlet oxygen such as sodium azide, histidine, and 2,5-dimethyl furan afforded substantial protection in a dose-dependent manner against AlPcTS-mediated photodestruction of cytochrome P450 and associated monooxygenase activities, and photoenhancement of lipid peroxidation under both in vivo and in vitro conditions. These results suggest that lipid-rich microsomal membranes may be the potential targets of cell injury by AlPcTS-based PDT and that this process is mediated by singlet oxygen.

Animals↗
PubMed1992

Tea components: antimutagenic and anticarcinogenic effects.

BACKGROUND: Tea from the Camellia sinensis species of the Theaceae family is one of the most ancient and, next to water, the most widely consumed beverage in the world. Since tea contains several polyphenols and since several other naturally occurring dietary polyphenols have shown antimutagenic effects in bacteria and anticarcinogenic effects in animal bioassay systems, we studied whether polyphenols extracted from Chinese green tea (GTP) also possess antimutagenic and anticarcinogenic effects. RESULTS: GTP and its constituent epicatechin derivatives were found to interact with hepatic cytochrome P450 (P450) and inhibited the P450-dependent mixed-function oxidase enzymes in skin and liver. GTP and its epicatechin derivatives exhibited antimutagenic effects in several test systems. GTP showed substantial anti-skin-tumor-initiating and anti-skin-tumor-promoting activities when assessed in murine skin tumorigenesis bioassay systems. In these model systems polyaromatic hydrocarbons, benzo[a]pyrene (BP), 3-methyl-cholanthrene, 7,12-dimethylbenz[a]anthracene, and (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (an ultimate carcinogenic metabolite of BP) were used as model skin carcinogens. The feeding of GTP in drinking water to SKH-1 hairless mice also afforded significant protection against ultraviolet-B-radiation-induced skin photocarcinogenesis. CONCLUSIONS: These data suggest that tea components possess antimutagenic and anticarcinogenic effects, and that they could protect humans against the risk of cancer by environmental agents.

Animals↗
PubMed1992

(-)-Epigallocatechin-3-gallate in Camellia sinensis leaves from Himalayan region of Sikkim: inhibitory effects against biochemical events and tumor initiation in Sencar mouse skin.

Recently, we and others showed that the components of green tea may be useful cancer chemopreventive agents. It has been suggested that (-)-epigallocatechin-3-gallate (EGCG), the major constituent in green tea, may possess antitumor-promoting and/or anticarcinogenic effects in rodent tumor bioassay systems. During the chemical analysis of various green tea products, we found a traditionally preserved preparation of green tea used by tribes in the Himalayan region of Sikkim, India that was rich in EGCG. EGCG was isolated from this tea product, and its inhibitory effects were evaluated against the binding of topically applied 3H-labeled polycyclic aromatic hydrocarbons (PAHs) to epidermal DNA and 12-O-tetradecanoylphorbol-13-acetate (TPA) caused induction of epidermal ornithine decarboxylase (ODC) activity in Sencar mice, the short-term markers of tumor initiation and tumor promotion, respectively. Preapplication of EGCG resulted in significant inhibition (p less than 0.05) in the binding of [3H]PAH to epidermal DNA. Similarly, the topical application of EGCG resulted in significant inhibition (p less than 0.005) in TPA-caused induction of epidermal ODC activity. In further studies, we assessed the anti-skin tumor-initiating effect of EGCG in Sencar mice in an initiation-promotion protocol. The application of EGCG before challenge with 7,12-dimethylbenz[a]anthracene as tumor initiator resulted in significant reduction both in percentage of mice with tumors and number of tumors per mouse compared with a non-EGCG-pretreated group of animals. The results of the present study suggest that the green tea preparation from Sikkim may be a good source for the isolation of EGCG and that this compound may have significant potential as a cancer chemopreventive agent.

Administration, Cutaneous↗
PubMed1992

Purification and molecular characterization of beta-naphthoflavone-inducible cytochrome P-450 from rat epidermis.

This study was designed to characterize epidermal cytochrome P-450 (P-450) induced by skin application of beta-naphthoflavone (beta-NF). Topical application of beta-NF (40 mg/kg) to rats resulted in a 2.6-times increase in epidermal P-450 content and a 3--14-times increase in epidermal monooxygenase activities. The purified epidermal P-450 showed a major band at 54 kDa on SDS-PAGE, which comigrated with hepatic P-4501A1 and cross-reacted with monoclonal and polyclonal antibodies specific to P-4501A1. The specific content of purified epidermal P-450 was 1.53 nmol/mg protein, representing 42-times purification. HPLC analysis of the purified epidermal P-450 showed similar elution profile and retention time as that of hepatic P-4501A1. The purified preparation efficiently catalyzed-benzo(a)pyrene hydroxylation when reconstituted with purified NADPH--P-450 reductase and phospholipid. Peptide fingerprint analysis of the purified epidermal P-450 and hepatic P-4501A1 showed similar monoclonal antibody 1-7-1 reacting epitopes. Partial N-terminal amino acid sequence analysis of purified epidermal P-450 showed complete homology with the known sequence of P-4501A1. Similarly, HPLC analysis of tryptic digest of purified epidermal P-450 and hepatic P-4501A1 showed identical peptide peaks with comparable retention times. N-terminal amino acid sequence analysis of three randomly selected tryptic peptides showed complete homology with the known sequence of P-4501A1. These results indicate that rat epidermal P-450 induced by beta-NF is similar to hepatic P-4501A1.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1992

Photodynamic therapy of chemically- and ultraviolet B radiation-induced murine skin papillomas by chloroaluminum phthalocyanine tetrasulfonate.

Photodynamic therapy (PDT) of cancer combines irradiation of tumors with visible light following selective uptake of the photosensitizer by the tumor cells. PhotofrinR-II (Pf-II) is the only photosensitizer which is in clinical use in PDT, whereas chloroaluminum phthalocyanine tetrasulfonate (AlPcTS) has also shown promise in preclinical studies. In most such studies, the effectiveness of the photosensitizers has been assessed in implanted tumor model systems rather than in model systems where tumors are allowed to grow in their own connective tissue matrix. In this study the pharmacokinetics, tumor ablation capability and cutaneous photosensitization response of AlPcTS have been assessed in mice bearing chemically- and ultraviolet B radiation (UVB)-induced benign skin papillomas. When tumor-bearing animals were injected intraperitoneally with AlPcTS (5 mg/kg body wt), maximum tumor:normal skin ratio of 2.4 was observed at 48 h, at which time the mice were irradiated within the absorption spectrum of the photosensitizer. In tumor ablation studies with SENCAR mice bearing chemically-induced skin tumors, AlPcTS resulted in greater than 80% ablation in tumor volume at 20 days post-irradiation. In cutaneous photosensitization response, AlPcTS produced only transient effects (no effect after 24 h) in SENCAR mice. Pharmacokinetics data, tumor ablation effects and cutaneous photosensitization response of AlPcTS were comparable in SKH-1 hairless mice bearing UVB-induced skin tumors. Our data indicate that AlPcTS produces significant photodynamic effects towards the ablation of murine skin tumors, and that it does not produce prolonged cutaneous photosensitivity.

Animals↗
PubMed1991

Antimutagenic and antitumorigenic activities of nordihydroguaiaretic acid.

Nordihydroguaiaretic acid (NDGA), which occurs in the resinous exudates of many plants is used as an antioxidant in fats and oils. In this study we show that NDGA inhibited the mutagenicity of methyl methanesulfonate, benzo[a]pyrene (BP), 2-aminofluorene, and aflatoxin B1 in Salmonella typhimurium strain TA100 or TA98 in the absence and presence of rat hepatic microsomal activation system. The addition of NDGA during and after nitrosation of methylurea (MU) resulted in a dose-dependent inhibition of mutagenicity induced by nitrosation products of MU. In a 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, pretreatment of animals with NDGA prior to DMBA application, afforded significant protection against skin tumorigenicity in female SENCAR mice. In additional studies, skin application of NDGA also inhibited the binding of topically applied [3H]BP and [3H]DMBA to epidermal DNA. When assessed in the anti-tumor promotion protocol, pretreatment of animals with NDGA before each application of TPA in DMBA-initiated mouse skin, resulted in 72% decrease in the total number of tumors when compared to non-NDGA pretreated animals. The possible mechanism(s) of the antimutagenic and anti-tumorigenic activities may be due to the multiple effects of NDGA as inhibitor of the carcinogen metabolism and DNA-adduct formation, scavenger of carcinogen free radicals, and as inhibitor of TPA-induced ornithine decarboxylase activity.

Animals↗
PubMed1991

Involvement of singlet oxygen in chloroaluminum phthalocyanine tetrasulfonate-mediated photoenhancement of lipid peroxidation in rat epidermal microsomes.

In recent studies chloroaluminum phthalocyanine tetrasulfonate (AlPCTS) has been shown to be an effective photosensitizer for the tumor necrosis in a modality known as photodynamic therapy, but the mechanism of photodynamic effect of AlPCTS is poorly understood. In this study, in vitro incubation of rat epidermal microsomes with AlPCTS followed by exposure to red light (approximately 675 nm) resulted in an increase in ADP/iron-supported lipid peroxidation, a measure of membrane damage. This photodestructive effect was found to be dependent on both the duration of light exposure and the dose of AlPCTS. Studies employing various quenchers of reactive oxygen species revealed that scavengers of singlet oxygen (histidine, 2,5-dimethylfuran, beta-carotene and sodium azide) afforded substantial protection (up to 90%) of photoenhancement whereas the scavengers of hydrogen peroxide (catalase), superoxide anion (superoxide dismutase), and hydroxyl radical (sodium benzoate, mannitol and ethanol) were ineffective in this regard. Our data indicate that AlPCTS-mediated photodestruction mainly involves a type II reaction via singlet oxygen formation and suggest that the latter could play a significant role in the tumor necrosis evoked by AlPCTS and light.

Animals↗
PubMed1991

Inhibition of mouse skin tumor-initiating activity of DMBA by chronic oral feeding of glycyrrhizin in drinking water.

Licorice (Glycyrrhiza glabra), a Mediterranean plant, has been used as an antidote, demulcent, and elixir folk medicine for generations in China. The main water-soluble constituent of licorice is glycyrrhizin (GL), which has been shown to possess several pharmacological properties. In this study, we show that oral feeding of GL to Sencar mice resulted in substantial protection against skin tumorigenesis caused by 7,12-dimethyl-benz [a]anthracene (DMBA) initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. The latent period prior to the onset of tumor development was considerably prolonged in GL-fed animals compared with animals not fed GL and resulted in significant decrease in the number of tumors per mouse, during and at the termination of the experiment. Oral feeding of GL in drinking water also resulted in inhibition in the binding of topically applied [3H]benzo[a]pyrene and [3H]DMBA to epidermal DNA. The possible mechanism(s) of the antitumor-initiating activity may be due to the involvement of GL as inhibitor of the carcinogen metabolism followed by DNA adduct formation. Our results suggest that GL possesses considerable antitumorigenic activity and could prove useful in protecting some forms of human cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Metabolism of benzo[a]pyrene by human melanocytes in culture.

Benzo[a]pyrene (B[a]P) is a ubiquitous environmental pollutant and known skin carcinogen. In the present study, in vitro addition of [3H]B[a]P to normal human melanocytes in culture, isolated from adult human skin, resulted in the metabolism of [3H]B[a]P both intracellularly and extracellularly. HPLC analysis showed that [3H]B[a]P-9,10- and 7,8-diol were the major intracellular and extracellular metabolites followed by 3,6-quinone, 9-hydroxy and 3-hydroxy metabolites. Significant amounts of the [3H]B[a]P metabolites were found to be present in the sonicated cell suspension and culture medium as the glucuronide and sulfate conjugates. In total 37.3% of the [3H]B[a]P added in the culture medium was metabolized by melanocytes, of which 21.1% was quantified as the intracellular and 16.2% as the extracellular metabolites. Our data show that human melanocytes are capable of metabolizing B[a]P.

Benzo(a)pyrene↗
PubMed1991

All-trans retinoic acid protects against conversion of chemically induced and ultraviolet B radiation-induced skin papillomas to carcinomas.

It is becoming increasingly clear that cutaneous carcinogenesis in murine skin is a stepwise process comprising of initiation, promotion and progression. Most of the papillomas induced by an initiation-promotion protocol regress, while a few of them progress to malignant carcinomas. Progression of benign tumors into malignant cancer is critical since the latter lesions are capable of metastatic spread and eventual death. Inhibitors of the conversion process are therefore likely to be useful as cancer chemopreventive agents. All-trans retinoic acid (RA) is a known regulator of cellular proliferation and differentiation, and a known inhibitor of tumor promotion in murine skin. In this study we assessed the effect of topical application of RA on conversion of benign skin papillomas to malignant carcinomas. Papillomas were induced in SENCAR mice by topical application of 7,12-dimethylbenz[a]anthracene (DMBA) as tumor initiator followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) as tumor promoter. In SKH-1 hairless mice papillomas were induced by thrice weekly exposure to ultraviolet B (UVB) radiation. At 18 (DMBA/TPA group) and 25 (UVB group) weeks papilloma yield stabilized and no new tumors developed. Beginning at the 20th week (DMBA/TPA group) and at the 27th week (UVB group), malignant conversion was achieved by twice weekly topical application of TPA or free radical-generating compounds benzoyl peroxide (BPO), 2,2-azobis(2-amidinopropane) (ABP) and tert-butyl peroxybenzoate (BPB). Application of RA (10 micrograms/animal) 1 h prior to skin application of TPA, BPO, ABP or BPB afforded significant protection (up to 70%) only against malignant conversion mediated by free radical-generating compounds in both chemically induced and UVB-induced benign skin papillomas. On the other hand, preapplication of RA was less effective in the suppression of spontaneous malignant conversion in vehicle-treated animals. These results suggest that, in addition to their anti-tumor promoting effects, retinoids may also act as anti-carcinogens by inhibiting the process of malignant conversion induced by free radical-generating compounds.

Animals↗
PubMed1991

Inhibition of mutagenicity in Salmonella typhimurium and skin tumor initiating and tumor promoting activities in SENCAR mice by glycyrrhetinic acid: comparison of 18 alpha- and 18 beta-stereoisomers.

Licorice has been used as medicine and as sweetening agent in food products. The major water-soluble constituent of licorice is glycyrrhizin (GL), an oleanane triterpenoide, which is known to be partly hydrolyzed by glucuronidase to its aglycone glycyrrhetinic acid (GA) which exists in 18 alpha (alpha-GA) and 18 beta (beta-GA) stereoisomeric forms. In this study alpha-GA and beta-GA were found to inhibit the mutagenicity of benzo[a]pyrene (B[a]P), 2-aminofluorene and aflatoxin B1 in Salmonella typhimurium TA98 and TA100. beta-GA was more effective than alpha-GA as an antimutagen. In the two-stage skin tumorigenesis protocol using 7,12-dimethylbenz[a]anthracene (DMBA) as the tumor initiating agent followed by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate as tumor promoter, pretreatment of SENCAR mice with alpha-GA or beta-GA resulted in significant protection against tumor initiation as well as tumor promotion. As an anti-tumor initiating agent, beta-GA was found to be more effective than alpha-GA. Similarly, topical application of beta-GA was found to be more effective than alpha-GA in inhibiting the binding of both [3H]B[a]P and [3H]DMBA to epidermal DNA. However, as an anti-tumor promoter, alpha-GA and beta-GA showed comparable effects. Our results suggest that both alpha-GA and beta-GA possess substantial anti-skin tumor initiating and anti-skin tumor promoting activities.

Animals↗
PubMed1991

Protection against ultraviolet B radiation-induced photocarcinogenesis in hairless mice by green tea polyphenols.

Our recent studies have shown that polyphenols present in green tea (GTP) possess significant antigenotoxic activity and afford protection against polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice. In this study we assessed the effect of oral feeding and topical application of GTP on ultraviolet B (UVB) radiation-induced skin carcinogenesis in female SKH-1 hairless mice. Chronic oral feeding of GTP (0.1%, w/v) in drinking water resulted in significantly (P less than 0.01) lower tumor yield (percent of animals with tumors and number of tumors per mouse) and extended TDT50 (P less than 0.05), as compared to animals receiving normal drinking water. Topical application of GTP before UVB irradiation also afforded protection against photocarcinogenesis; however, the protective response was lower than that observed by oral feeding of GTP in drinking water. These results, in conjunction with our prior publications, suggest that consumption of green tea may reduce the risk of some forms of human cancer induced by both physical and chemical environmental carcinogens.

Animals↗
PubMed1991

Glutathione S-transferases in human and rodent skin: multiple forms and species-specific expression.

The glutathione S-transferases (GST) are a family of widely distributed multifunctional detoxification enzymes that catalyze the reaction between reduced glutathione and a variety of electrophiles. Of interest is the fact that several extracutaneous tissues exhibit a distinct spectrum of isozymes that are expressed in a highly controlled fashion. Despite the fact that the skin is continuously exposed to numerous injurious agents, little is known about the expression of GST isozymes and their role in metabolism of physiologic and xenobiotic substrates in cutaneous tissue. Using specific polyclonal antibodies to the Alpha, Mu, and Pi classes of GST, we identified their expression in rat, mouse, and human skin cytosol. In each species, GST isozymes expressed activities towards 1-chloro-2,4-dinitrobenzene, benzo(a)pyrene 4,5-oxide, styrene 7,8-oxide, leukotriene A4, and ethacrynic acid, but not towards bromosulfophthalein and cumene hydroperoxide. Western blot analysis indicated the predominant expression of Pi isozyme in all three species. Alpha class of isozyme(s) was present only in human skin, whereas Mu class of isozyme(s) was detected only in rat and mouse skin. Similarly, in normal and transformed cultured human keratinocytes Pi was the predominant isozyme. In situ localization studies using immunohistochemical techniques confirmed the observations of Western blotting. In mouse skin, Pi and Mu isozyme(s) were found to be predominantly localized in sebaceous glands, whereas no reactivity was observed with the Alpha class of isozymes. Our data show that multiple forms of GST exist in rodent and human skin and that GST Pi is the predominant isozyme in each species. Furthermore, cutaneous GST can metabolize both endogenous substrates and foreign compounds.

Animals↗
PubMed1991

Specific high-affinity binding of fatty acids to epidermal cytosolic proteins.

Cytosol from rat, mouse, and human skin or rat epidermis was incubated with [3H]arachidonic acid, [14C]retinoic acid, [14C]oleic acid, [3H]leukotriene A4, [3H]prostaglandin E2 (PGE2) or [3H] 15-hydroxyeicosatetraenoic acid (15-HETE), and protein-bound ligands were separated using Lipidex-1000 at 4 degrees C to assess the binding specificity. The binding of oleic acid and arachidonic acid with rat epidermal cytosol was rapid, saturable, and reversible. Binding of oleic acid was competed out with the simultaneous addition of other ligands and found to be in the following order: arachidonic acid greater than oleic acid greater than linoleic acid greater than lauric acid greater than leukotriene A4 greater than 15-HETE = PGE1 greater than PGE2 = PGF2. Scatchard analysis of the binding with arachidonic acid, oleic acid, and retinoic acid revealed high-affinity binding sites with the dissociation constant in the nM range. SDS-PAGE analysis of the oleic acid-bound epidermal cytosolic protein(s) revealed maximum binding at the 14.5 kDa region. The presence of the fatty acid-binding protein in epidermal cytosol and its binding to fatty acids and retinoic acid may be of significance both in the trafficking and the metabolism of fatty acids and retinoids across the skin.

Animals↗
PubMed1991

Photodynamic therapy of murine skin tumors using Photofrin-II.

Photodynamic therapy (PDT) is a new experimental cancer therapy in which a photosensitizing chemical that selectively localizes within tumors is given to a tumor-bearing individual and the tumor is then irradiated by wavelengths within the visible spectrum of the photosensitizer. The only photosensitizer currently approved for human clinical trials is Photofrin-II (Pf-II). In most preclinical studies, the effectiveness of Pf-II has been assessed in implanted tumor models rather than in systems in which tumors are grown in their own connective tissue matrix. In this study, the pharmacokinetics, tumor ablation capability and cutaneous photosensitizing capacity of Pf-II were assessed in mice bearing chemically induced or ultraviolet B radiation (UVB)-induced benign skin neoplasms. Intraperitoneal administration of Pf-II (5 mg/kg body weight) to tumor-bearing animals showed maximum tumor: normal skin ratio of the photosensitizer at 72 h. When SENCAR mice bearing chemically induced tumors were irradiated with visible light corresponding to the absorption spectrum of the photosensitizer, up to 89% ablation in tumor volume at 20 d post-irradiation was observed. Animals treated with Pf-II and exposed to visible light showed significant cutaneous photosensitization for at least 6 d after-irradiation. Treatment of SKH-1 hairless mice bearing UVB-induced cutaneous neoplasms with Pf-II exhibited similar pharmacokinetics, skin tumor ablation effects and cutaneous photosensitivity. Our data indicate that Pf-II has significant activity towards the ablation of murine skin benign tumors grown in their own tissue matrix, suggesting that such a murine skin tumor model system could be valuable in evaluating the photodynamic effects of newly developed photosensitizers.

Animals↗