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Biomedical subjects

D R Bickers

Publications and source records attributed to D R Bickers.

At least 109 records · Page 6Linked to original sources
PubMed1985

Effect of ellagic acid on hepatic and pulmonary xenobiotic metabolism in mice: studies on the mechanism of its anticarcinogenic action.

Our recent studies have shown that ellagic acid, a naturally occurring dietary plant phenol, protects BALB/c mice against 3-methylcholanthrene-induced skin tumorigenesis. To further elucidate the mechanism of the antineoplastic action of ellagic acid its effect on hepatic and pulmonary benzo[a]pyrene (BP) metabolism, cytochrome P-450-dependent monooxygenases and glutathione S-transferase activities were studied in BALB/c mice. Chronic oral feeding of the compound in drinking water (0.3 mg/l for 16 weeks) or acute intraperitoneal administration (50 mg/kg for five consecutive days) of ellagic acid resulted in 20-25% decreases in hepatic and pulmonary cytochrome P-450 levels. Hepatic and pulmonary aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase activities in both groups of ellagic acid-treated animals were 33-52% and 28-43% lower than their respective non-ellagic acid-treated controls. Hepatic as well as pulmonary aminopyrine N-demethylase and epoxide hydrolase activities were unchanged in both groups of ellagic acid-treated mice. Hepatic glutathione S-transferase activity towards BP-4,5-oxide or 1-chloro-2,4-dinitrobenzene as substrates was found to be enhanced 51-79% and 38-58% in both groups of animals. H.p.l.c. analysis of organic solvent-soluble metabolites of BP by liver and lung microsomes indicated a substantial inhibition of diol formation (including BP-7,8-diol), as well as of phenols and quinones. In liver, these inhibitory effects were more pronounced after oral feeding than after intraperitoneal administration. Our results indicate that both acute and chronic administration of ellagic acid inhibits BP metabolism and/or enhances glutathione S-transferase activity. Thus the modulation of polycyclic aromatic hydrocarbon metabolism by ellagic acid may be related to the anticarcinogenic effects of this compound.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1985

Altered patterns of cutaneous xenobiotic metabolism in UVB-induced squamous cell carcinoma in SKH-1 hairless mice.

Cutaneous xenobiotic metabolizing enzymes including aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECD), epoxide hydrolase (EH) and glutathione S-transferase (GST) activities were examined in SKH hairless mice chronically irradiated with UVB to induce squamous cell carcinoma (SCC). Enzyme activities in irradiated tumor-bearing skin were compared to those present in the skin of nonirradiated control animals as well as in unirradiated non-tumor bearing skin sites of the SCC-bearing mice. The inducibility of skin AHH and ECD in each set of animals was assessed following a single topical application of coal tar (1 ml/100 g). Enzyme-mediated binding of [3H]benzo(a)pyrene (BP) and its metabolite 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE-I) to epidermal DNA was also evaluated. Basal AHH and ECD activities in microsomes from UVB-irradiated SCC-bearing dorsal skin were 4.6- and 4.8-fold lower than those in dorsal skin of nonirradiated control animals. Enzyme activities in non-tumor bearing ventral skin from the UVB-irradiated SCC-bearing mice also were 2.2 to 2.8-fold lower as compared to activities in the nonirradiated control animals. The reduction in AHH activity paralleled the levels of enzyme-mediated binding of radiolabeled BP metabolites and of BPDE-I to epidermal DNA. GST activity was found to be increased (173%) in non-tumor bearing ventral skin of UVB-irradiated mice whereas no difference in activity between SCC-bearing dorsal skin and dorsal skin of control animals could be detected. EH activity was unchanged in each group of animals. Treatment with topically applied coal tar resulted in higher inducibility of AHH and ECD in both SCC-bearing (13-fold) as well as in non-tumor skin sites (6-fold) of UVB-irradiated mice than in skin of control animals (3-fold). Coal tar application also increased the covalent binding of [3H]BP and of the metabolite BPDE-I to skin DNA. This was greater in SCC-bearing dorsal skin (119-129%) than in nonirradiated skin of control animals (48-62%). Our studies suggest that the metabolism of BP by cutaneous cytochrome P-450 dependent monooxygenases is impaired in skin of mice irradiated chronically with UVB. The higher inducibility of these monooxygenases by topically applied coal tar and the enhancement of the associated enzyme-mediated covalent binding of BP metabolites and BPDE-I to epidermal DNA indicate that repetitive exposure of mammalian skin to UVB radiation can profoundly alter the activity and the inducibility of drug and carcinogen metabolizing enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Topical↗
PubMed1985

Role of active oxygen species in the photodestruction of microsomal cytochrome P-450 and associated monooxygenases by hematoporphyrin derivative in rats.

The cytochrome P-450 in hepatic microsomes prepared from rats pretreated with hematoporphyrin derivative was shown to be rapidly destroyed in the presence of long-wave ultraviolet light. The photocatalytic destruction of the heme-protein was dependent on both the dose of ultraviolet light and of hematoporphyrin derivative administered to the animals. The destructive reaction was accompanied by increased formation of cytochrome P-420, loss of microsomal heme content, and diminished catalytic activity of cytochrome P-450-dependent monooxygenases such as aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase. The specificity of the effect on cytochrome P-450 was confirmed by the observation that other heme-containing moieties such as myoglobin and cytochrome c were not susceptible to photocatalytic destruction. The destruction of cytochrome P-450 was a photodynamic process requiring oxygen since quenchers of singlet oxygen, including 2,5-dimethylfuran, histidine, and beta-carotene, each substantially diminished the reaction. Scavengers of superoxide anion such as superoxide dismutase and of H2O2 such as catalase did not protect against photodestruction of cytochrome P-450, whereas inhibitors of the hydroxyl radical, including benzoate, mannitol, and ethyl alcohol, did afford protection. These results indicate that lipid-rich microsomal membranes and the heme-protein cytochrome P-450 embedded therein are potential targets of injury in cells exposed to hematoporphyrin derivative photosensitization.

Animals↗
PubMed1985

Photoenhancement of lipid peroxidation associated with the generation of reactive oxygen species in hepatic microsomes of hematoporphyrin derivative-treated rats.

Hepatic microsomes prepared from rats pretreated with hematoporphyrin derivative (HPD) undergo rapid enhancement of lipid peroxidation in the presence of solar radiation (approximately 400 nm). Quenchers of singlet oxygen, including 2,5-dimethylfuran, histidine, and beta-carotene, and inhibitors of the hydroxyl radical, including benzoate, mannitol, and ethanol, largely protected against the enhancement of lipid peroxidation caused by HPD photosensitization. Catalase, a scavenger of hydrogen peroxide and superoxide dismutase, a scavenger of superoxide anion, had little or no protective effect against HPD-photosensitized enhancement of lipid peroxidation. Our data indicate that in vitro irradiation of hepatic microsomes prepared from HPD-treated rats results in the generation of both singlet oxygen and hydroxyl radical. These reactive moities are associated with a rapid increase in microsomal lipid peroxidation which may explain the unique susceptibility of membranous components of cells to this type of phototoxic injury.

Animals↗
PubMed1985

Sun-induced disorders.

Photosensitivity diseases frequently occur as a result of sun exposure in individuals with inherited and acquired disorders. Several of these disorders may manifest acute cutaneous manifestations that bring the patient to the emergency room. The more common disorders that may be seen in this setting include sunburn, lupus erythematosus, porphyria, photosensitivity dermatitis, and polymorphous light eruption. The diagnosis can frequently be suspected on the basis of a careful history and physical examination. Specialized diagnostic procedures available to the dermatologist may assist in making the correct diagnosis. Effective treatment is available for many of these disorders.

Adult↗
PubMed1984

Plant phenols as in vitro inhibitors of glutathione S-transferase(s).

Ellagic acid, a commonly occurring plant phenol, was shown to be a potent in vitro inhibitor of GSH-transferase(s) activity. Other plant phenols such as ferrulic acid, caffeic acid and chlorogenic acid also showed a concentration dependent inhibition of GSH-transferase(s) activity. The I50 values of ellagic acid, caffeic acid, chlorogenic acid and ferrulic acid were 8.3 X 10(-5)M, 14.0 X 10(-5)M, 20.0 X 10(-5)M and 22.0 X 10(-5)M respectively, suggesting that ellagic acid is the most potent inhibitor of all the four studied plant phenols. At 55 microM concentration of ellagic acid, a significant inhibition (35-47%) was observed on GSH-transferase activity towards CDNB, p-nitrobenzyl chloride and 1,2-epoxy-3-(p-nitrophenoxy)propane as substrates. Ellagic acid inhibited GSH-transferase(s) activity in a non-competitive manner with respect to CDNB while with respect to GSH it inhibited the enzyme activity in a competitive manner. Other phenolic compounds purpurogallin , quercetin, alizarin and monolactone also showed a concentration dependent inhibition of the enzyme activity with a I50 of 0.8 X 10(-5)M, 1.0 X 10(-5)M, 8.0 X 10(-5)M and 16.0 X 10(-5)M respectively. These inhibitors of GSH-transferase(s) activity should be useful in studying the in vitro enzyme mediated reactions of exogenous and endogenous compounds.

Animals↗
PubMed1984

Enhancement of bleomycin-mediated DNA damage by epidermal microsomal enzymes.

The role of epidermal microsomal enzymes in catalyzing bleomycin-mediated chain breakage in calf-thymus DNA and in DNA isolated from neonatal rat epidermis was studied. Aerobic incubation of bleomycin with epidermal microsomes, epidermal or calf-thymus DNA and NADPH caused substantial chain breakage of the DNA which was dependent upon concentrations of drug, microsomal protein and NADPH. The reactive oxygen scavenger superoxide dismutase, the metal chelator EDTA, and cytochrome c each inhibited the enzyme-mediated chain breakage reaction. Scavengers of hydrogen peroxide and hydroxyl radicals, including catalase and benzoate and inhibitors of microsomal cytochrome P-450-dependent monooxygenases such as 1-benzylimidazole, metyrapone and alpha-naphthoflavone, had no inhibitory effects on bleomycin-mediated DNA chain breakage. In contrast, ascorbic acid significantly enhanced DNA damage by bleomycin. These studies indicate that mammalian epidermis possesses membrane-bound enzyme activity capable of enhancing bleomycin-mediated chain breakage of DNA and that oxidation/reduction of adventitious iron and generation of reactive oxygen participate in the reaction. These responses in the epidermis could directly relate to the mechanism of action of intralesional injections of bleomycin which are used quite effectively in the management of recalcitrant human warts. Either epidermal or wart virus DNA or both could be targets for this pharmacologic effect of the drug which is augmented by epidermal microsomal enzymes.

Animals↗
PubMed1984

Protection against 3-methylcholanthrene-induced skin tumorigenesis in Balb/C mice by ellagic acid.

Topical application of ellagic acid, a naturally occurring dietary plant phenol, to Balb/C mice resulted in significant protection against 3-methylcholanthrene (MCA)-induced skin tumorigenesis. Ellagic acid was found to be an effective inhibitor of tumor formation whether the tumor data are considered as percent mice with tumors, cumulative number of tumors, tumors per mouse or tumors per tumor bearing animal as a function of the number of weeks on test. By 8, 10, 12, 14, and 16 weeks of testing, the number of tumors per mouse in the group receiving MCA alone was 2.0, 3.4, 4.0, 4.9 and 5.3, respectively, whereas the corresponding numbers in the group receiving MCA plus 2 mumol ellagic acid were 0, 0.3, 0.4, 0.6 and 1.2, respectively. At the termination of the experiment (16 weeks) aryl hydrocarbon hydroxylase (AHH) activity in skin and liver and the extent of 3H-BP-binding to skin, liver and lung DNA were determined and both of these parameters were found to be significantly inhibited in the animals treated with ellagic acid. These results indicate that ellagic acid can inhibit the metabolism of polyaromatic hydrocarbons and modulate skin carcinogenesis induced by these chemicals.

Animals↗
PubMed1984

Bullous dermatosis caused by Staphylococcus aureus in locus minoris resistentiae.

A case of Staphylococcus aureus--induced bullous dermatosis limited to the sites of glucocorticosteroid-induced striae atrophicae is described. Skin with compromised mechanical integrity may be more susceptible to disruption by invasion of bacteria and/or by their exotoxin. The pathogenesis of striae atrophicae and the mechanism of blister formation by S. aureus are reviewed in an effort to relate these two phenomena.

Administration, Topical↗
PubMed1984

Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine.

Dermatomyositis (DM) is a collagen vascular disease with prominent cutaneous findings. Although the myositis often responds to therapy with corticosteroids and/or immunosuppressives, the cutaneous disease may not respond. Seven patients with cutaneous lesions of DM that had not responded to therapy were treated with hydroxychloroquine in an open study. Three patients had idiopathic DM, one had DM without myositis, one had DM with malignancy, and one had adolescent DM. The response to the addition of hydroxychloroquine was good in all of the patients, and three had total resolution of their skin lesions. In two patients the corticosteroid dosage could be tapered. Therapy with hydroxychloroquine did not appear to have any beneficial effect on the myositis. We conclude that hydroxychloroquine may have a role as an adjuvant to the therapy of patients with cutaneous lesions of DM.

Adenocarcinoma↗
PubMed1984

Ellagic acid: a potent naturally occurring inhibitor of benzo[a]pyrene metabolism and its subsequent glucuronidation, sulfation and covalent binding to DNA in cultured BALB/C mouse keratinocytes.

The metabolism of [3H]benzo[a]pyrene (BP) by cultured primary keratinocytes prepared from BALB/C mouse epidermis was found to be largely inhibited by the dietary plant phenol, ellagic acid. Varying concentrations of ellagic acid added to the keratinocyte cultures resulted in a dose-dependent inhibition of the cytochrome P-450-dependent monooxygenases aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin-O-deethylase (ECD). The major organic solvent-extractable metabolites found intracellularly in the cultured cells were trans-7,8-dihydro-7,8-dihydroxybenzo[a]-pyrene (BP-7,8-diol) and 3-hydroxybenzo[a]pyrene (3-OH-BP), although small amounts of 9-hydroxybenzo[a]pyrene, quinones and trans-9,10-dihydro-9,10-dihydroxybenzo[a]-pyrene (BP-9,10-diol) were also present. The major organic solvent-extractable metabolites found in the extracellular culture medium were BP-7,8-diol and BP-9,10-diol, with smaller quantities of unconjugated phenols and quinones. The major intracellular and extracellular water-soluble metabolites of BP were conjugated with glucuronide (primarily 3-OH-BP and several BP-quinones), and to a lesser extent with sulfate (primarily BP-7,8-diol). Both intracellular and extracellular metabolism of organic solvent-extractable and water-soluble conjugates was significantly inhibited by ellagic acid in a dose-dependent manner. The intracellular enzyme-mediated binding of BP to mouse keratinocyte DNA was also largely inhibited in a dose-dependent fashion by ellagic acid. Our results indicate that cultured primary mouse keratinocytes offer a useful model system for studying factors affecting the metabolic activation and detoxification of polycyclic aromatic hydrocarbon carcinogens in the epidermis, and that polyphenolic compounds such as ellagic acid may prove useful in modulating the risk of cutaneous cancer that results from exposure to these environmental chemicals.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1984

In vivo metabolism of topically applied benzo[a]pyrene-4,5-oxide in neonatal rat skin.

The metabolism of benzo[a]pyrene (BP)-4,5-oxide in the skin and liver of neonatal rats was studied after topical application of the arene oxide in vivo. The metabolism of BP-4,5-oxide was time-dependent and showed a 2-h maximum for BP-4,5-dihydrodiol formation in both skin and liver. Product formation was also dose-dependent. Inhibitors of epoxide hydrolase such as clotrimazole, 1,1,1,-trichloropropene oxide, and cyclohexene oxide largely abolished the formation of BP-4,5-dihydrodiol. The rapid biotransformation of arene oxides such as BP-4,5-oxide in the skin emphasizes the potential importance of epoxide hydrolase in the activation and inactivation of polycyclic aromatic hydrocarbons. Furthermore, the topically applied arene oxide also penetrated the skin and was rapidly metabolized in the liver as well.

Administration, Topical↗
PubMed1984

Aryl hydrocarbon hydroxylase, epoxide hydrolase, and benzo[a]-pyrene metabolism in human epidermis: comparative studies in normal subjects and patients with psoriasis.

Prior studies have shown that human skin possesses a cytochrome P-450-dependent microsomal enzyme that is capable of metabolizing drugs and polycyclic aromatic hydrocarbon (PAH) carcinogens. This study characterized benzo[a]pyrene (BP) metabolism in human epidermis of normal and psoriatic individuals. The basal level of the cytochrome P-450-dependent microsomal enzyme aryl hydrocarbon hydroxylase (AHH) and epoxide hydrolase (EH) were measured in freshly keratomed epidermis from 12 normal individuals and from uninvolved skin sites of 12 patients with psoriasis. The induction response of AHH following the in vitro addition of the PAH benz[a]anthracene (BA) was also assessed. The basal activity (mean +/- SE) of AHH in normal epidermis was 62.1 +/- 5.6 units (fmol 3-hydroxybenzo[a]pyrene, 3-OH-BP/min/mg protein) whereas the activity in uninvolved skin of psoriatic individuals was 62.9 +/- 5.1 units (NS), Epoxide hydrolase activity was 25.1 +/- 1.1 (pmol BP 4,5-diol/min/mg protein) unites in normal epidermis and 24.8 +/- 2.1 units in epidermis from patients with psoriasis (NS). Following addition of BA (100 microM), in vitro, AHH activity in normal epidermis increased by a mean value of 165% whereas activity in nonlesional epidermis of psoriatic individuals increased 320%. Kinetic studies in normal epidermis revealed that AHH reaction was linear up to 60 min and to 50 micrograms protein, had a pH optimum of 7.4, and the Km for BP was 0.62 microM. High-performance liquid chromatography (HPLC) confirmed that the pattern of metabolism of BP was quite similar in epidermal microsomes prepared from normal and psoriatic individuals, insofar as the formation of diols, phenols, and quinones was concerned. These studies indicate that human epidermis is capable of metabolizing BP and that there is no significant difference between normal individuals and patients with psoriasis insofar as basal AHH activity or total BP metabolism is concerned. Furthermore, the epidermal enzyme system in patients with psoriasis has a greater responsiveness to environmental PAH than does that of normal individuals.

Aryl Hydrocarbon Hydroxylases↗
PubMed1984

Epidermal benzo[a]pyrene metabolism and DNA-binding in Balb/C mice: inhibition by ellagic acid.

Topical application of ellagic acid, a common plant phenol, to control or to 3-methylcholanthrene (3-MC) pretreated Balb/C mice, resulted in significant inhibition of hepatic and epidermal microsomal aryl hydrogen hydroxylase activity, and of benzo[a]pyrene (BP) binding to epidermal and hepatic DNA in vivo. In vitro addition of ellagic acid (0.25 mM) to epidermal microsomal incubation systems from either control or 3-MC-treated animals resulted in 62-75% inhibition of BP binding to calf thymus DNA. These studies suggest that ellagic acid could prove useful in understanding and/or modulating polyaromatic hydrocarbon carcinogenesis.

Animals↗