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Biomedical subjects

D R Bickers

Publications and source records attributed to D R Bickers.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1988

In situ evidence for the involvement of superoxide anions in cutaneous porphyrin photosensitization.

Dihematoporphyrin ether, also known as Photofrin-II (Pf-II) is currently used in the diagnosis and management of a variety of epithelial neoplasms, in a modality known as photodynamic therapy (PDT). A major drawback of these porphyrins for PDT is their ability to evoke prolonged cutaneous photosensitization. The mechanism of tumor ablation and cutaneous photosensitization by these photosensitizers is thought to relate to the generation of one or more reactive oxygen species such as superoxide anion, singlet oxygen and hydroxyl radical. However, the role of these oxygen species has not been established unequivocally. In this study, the mechanism of Pf-II-mediated cutaneous photosensitization was examined using murine ear swelling as a marker. The mice treated with Pf-II and light demonstrated two-fold enhancement of ear swelling whereas animals treated with the SOD mimic, beta-carotene and dimethyl sulfoxide (DMSO) had considerably less ear swelling (p less than 0.01). The observed protective effect was dependent on the dose of each quencher and followed the pattern SOD mimic DMSO beta-carotene. The histopathologic alterations caused by Pf-II photosensitization were significantly alleviated by pretreatment with SOD mimic whereas beta-carotene and (DMSO) were less effective. Inhibitors of superoxide dismutase (sodium diethyldithiocarbamate) and catalase (hydroxyl amine and 3, amino 1,2,4-triazole) augmented Pf-II-mediated cutaneous photosensitization. These data provide the first in vivo evidence for the involvement of superoxide anion in cutaneous porphyrin photosensitization.

Animals↗
PubMed1988

Fecal protoporphyrin excretion in erythropoietic protoporphyria: effect of cholestyramine and bile acid feeding.

The effect of cholestyramine and bile acid feeding upon fecal, red blood cell, and plasma protoporphyrin levels was evaluated in a patient with erythropoietic protoporphyria and evidence of hepatic damage. After a basal period on a controlled diet, bile acids alone were administered (300-900 mg) daily for 9 days, followed by cholestyramine (12 g) plus bile acids (900 mg) daily for 7 days, and cholestyramine alone (12 g) daily for 6 days. There was no substantial change in either the red blood cell or plasma protoporphyrin concentrations during any treatment period. However, cholestyramine and cholestyramine combined with bile acids caused a threefold increase in fecal protoporphyrin excretion, whereas bile acids alone had no effect in this regard. After 1 yr of cholestyramine therapy, fecal excretion of protoporphyrin remained elevated with concurrent improvement in liver function tests and photosensitivity. This study indicates that cholestyramine but not bile acids can substantially increase protoporphyrin excretion and therefore may be capable of ameliorating the hepatotoxicity that may occur in selected patients with erythropoietic protoporphyria.

Bile Acids and Salts↗
PubMed1988

Screening for the developmental toxicity of retinoids: use of the sea urchin model.

Retinoids are being used increasingly in dermatologic practice. Fetal malformation is a major form of toxicity associated with certain retinoids. In this study, the developmental toxicity of isotretinoin, its metabolites, and a structurally related analog, tretinoin, were evaluated using the sea urchin model. The American sea urchin, Arbacia punctulata, completes its major developmental stages within 24 hr and has been previously utilized for screening human teratogens. The parent compound, isotretinoin, induced dose-dependent delayed rather than dysmorphic development of the sea urchin embryo. In contrast, its metabolites, 4-oxo-isotretinoin and 4-oxo-tretinoin, and the analog tretinoin induced strikingly dysmorphic development. This may indicate that the metabolites of isotretinoin, rather than the parent compound, may be responsible for the fetal abnormalities observed in the "isotretinoin teratogen syndrome." Therefore, the sea urchin model might serve as a discriminating and rapid screening test for identifying other potential developmentally toxic retinoids.

Animals↗
PubMed1988

Differential role of reactive oxygen intermediates in photofrin-I- and photofrin-II-mediated photoenhancement of lipid peroxidation in epidermal microsomal membranes.

Photoradiation therapy with porphyrins and light offers an alternative approach to the management of certain types of cancer. The mechanism of tissue destruction mediated by this modality is poorly understood. In this study, epidermal microsomes incubated in vitro with Photofrin-I (Pf-I) and Photofrin-II (Pf-II) followed by exposure to radiation (approximately 400 nm) resulted in increased (180%) NADPH-supported (enzymatic) as well as ADP/iron-supported (140%) (nonenzymatic) lipid peroxidative damage as measured by malondialdehyde formation. Lipid peroxidation by Pf-I and Pf-II was found to be differentially affected by quenchers of singlet oxygen (2,5-dimethylfuran, histidine, beta-carotene, ascorbic acid, and sodium azide), superoxide anion (superoxide dismutase), and the hydroxyl radical (sodium benzoate, mannitol, and ethanol). Catalase, a quencher of hydrogen peroxide, afforded significant protection only against Pf-II-enhanced lipid peroxidative damage while it had little effect against the Pf-I-mediated reaction. Deuterium oxide, which is known to increase the half-life of singlet oxygen, was found to enhance Pf-I-mediated lipid peroxidation but produced insignificant effects upon Pf-II-mediated photosensitization. Our results indicate that Pf-I and Pf-II, which are employed for the photodynamic therapy of malignant tumors, evoke membrane damage by generating different reactive oxygen species. The Pf-I-mediated photodestruction mainly involves a type II mechanism via singlet oxygen formation, whereas Pf-II-mediated photodestruction preferentially involves a type I mechanism by generating superoxide anions and hydroxyl radicals. Our data indicate that tumor necrosis evoked by porphyrins and light is likely due to the generation of reactive oxygen species.

Animals↗
PubMed1987

7-Ethoxyresorufin-O-deethylase activity in human hair roots: a potential marker for toxifying species of cytochrome P-450 isozymes.

Assay systems for the evaluation of carcinogen interaction with human tissues are essential for assessing cancer risk. Human hair roots (HHR) are a readily obtainable epithelial tissue source that have been employed for investigating inherited enzyme activities. In this study HHR were found to possess cytochrome P-450-dependent 7-ethoxyresorufin-O-deethylase (ERD) activity which measures cytochrome P-450 isoenzymes that are highly specific (in the order of greater than 95%) markers for the metabolic activation of many environmental carcinogenic substances such as the polycyclic aromatic hydrocarbons (PAHs). Topical application of PAHs (in liquor carbonis detergens) to the scalp of human volunteers was found to enhance the activity of this enzyme in freshly plucked hair roots. Oral and topical administration of ketoconazole to the same subjects resulted in an appreciable (up to 73%) inhibition of detectable enzyme activity. Our data suggest that measurement of ERD in HHR may be a useful marker for the study of toxifying species of cytochrome P-450 isozymes in human populations.

Carcinogens↗
PubMed1987

Induction of epidermal NAD(P)H:quinone reductase by chemical carcinogens: a possible mechanism for the detoxification.

NAD(P)H:quinone reductase, which plays an important role in the detoxification of carcinogenic metabolites as well as oxidative cellular damage, was found to be present in epidermal cytosol where its specific activity far exceeds (140-160%) the corresponding hepatic value. The effect of topical application of crude coal tar, 3-methylcholanthrene and polychlorinated biphenyl Aroclor 1254, on epidermal and hepatic cytosolic NAD(P)H:quinone reductase activities was investigated in neonatal rats, Sencar and athymic nude mice. A single topical application of each agent resulted in significant increases in epidermal (185%-389%) and hepatic (150-255%) enzyme activities. This inducible enzyme may play an important role in the detoxification of reactive quinone species during the course of malignant neoplasia and against oxidative cellular damage in skin.

Animals↗
PubMed1987

Cytochrome P-450 dependent metabolism of testosterone in rat skin.

The incubation of microsomes of whole skin, dermis and epidermis with 14C testosterone in the presence of NADPH resulted in the formation of 6 beta-, 7 alpha- and 16 alpha-testosterone. Maximum enzyme activity occurred in epidermal microsomes followed by dermis and whole skin. Epidermal testosterone hydroxylase activity required NADPH and oxygen and was found to be inhibited by SKF 525A and metyrapone. Our data strongly suggest that testosterone is metabolized by the cytochrome P-450 dependent monooxygenase in skin and provides the first evidence for an endogenous substrate for cytochrome P-450 in this tissue. The formation of several hydroxylated products further suggests the existence of multiple isozymes of cytochrome P-450 in rat skin. These studies provide additional evidence that target tissues may modulate their hormone levels by enzyme pathways that are locally regulated.

Animals↗
PubMed1987

Inhibition of epidermal xenobiotic metabolism in SENCAR mice by naturally occurring plant phenols.

Naturally occurring plant phenols such as tannic acid, quercetin, myricetin, and anthraflavic acid have been shown to inhibit the mutagenicity of several bay-region diol-epoxides of polycyclic aromatic hydrocarbons including benzo(a)pyrene (BP). The present study was designed to determine whether these plant phenols can alter epidermal cytochrome P-450-dependent monooxygenases in SENCAR mice. In vitro addition of these plant phenols to epidermal microsomal preparations inhibited aryl hydrocarbon hydroxylase (AHH) activity in a concentration-dependent manner. The 50% inhibitory concentrations for tannic acid, myricetin, quercetin, and anthraflavic acid ranged from 4.4 X 10(-5) M to 12.4 X 10(-5) M in microsomes prepared from control and 3-methylcholanthrene-pretreated animals. Of the plant phenols studied tannic acid was found to be the most potent inhibitor of epidermal AHH activity. Tannic acid, quercetin, myricetin, and anthraflavic acid exhibited a mixed type of inhibitory effect with Ki values of 81, 63, 135, and 165 microM, respectively. In vitro addition of these plant phenols (240 microM) to the incubation mixture prepared from control and 3-methylcholanthrene-treated animals resulted in varying degrees of inhibition of epidermal microsomal AHH (57-92%), ethoxycoumarin O-deethylase (19-58%), and ethoxyresorufin O-deethylase (33-85%) activities. High pressure liquid chromatographic analysis of the organic solvent-soluble metabolites of BP produced by epidermal microsomes indicated a substantial decrease in the formation of BP-diols (23-67%) and BP-phenols (29-57%) by each of the plant phenols. The formation of BP-7,8-diol was substantially inhibited (29-52%) by each of the plant phenols. Further in vivo studies showed that a single topical application of tannic acid, quercetin, and myricetin greatly diminished epidermal AHH (53-65%), ethoxycoumarin O-deethylase (30-68%), and ethoxyresorufin O-deethylase (66-97%) activities whereas anthraflavic acid was ineffective in this regard even when repeatedly applied. Our results indicate that plant phenols have substantial though variable inhibitory effects on epidermal monooxygenase activities and BP metabolism suggesting that these compounds may be capable of inhibiting the carcinogenic effects of polycyclic aromatic hydrocarbons in the skin.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1987

Inhibition of polycyclic aromatic hydrocarbon-DNA adduct formation in epidermis and lungs of SENCAR mice by naturally occurring plant phenols.

Naturally occurring plant phenols such as tannic acid, quercetin, myricetin, and anthraflavic acid are known to inhibit the mutagenicity of several bay-region diol-epoxides of polycyclic aromatic hydrocarbons (PAHs). The binding of bay-region diol-epoxides of PAHs to target tissue DNA is thought to be essential for the initiation of cancer by these compounds. In this study we investigated the effect of these plant phenols on PAH-DNA adduct formation in the epidermis and lung of SENCAR mice. In vitro addition of tannic acid, quercetin, myricetin, and anthraflavic acid (25 microM) to an incubation system containing epidermal microsomes prepared from either control or 3-methylcholanthrene-pretreated mice inhibited benzo(a)pyrene binding to calf thymus DNA by 63-64, 38-43, 36-37, and 27-33%, respectively. A single topical application of tannic acid, quercetin, myricetin, and anthraflavic acid at a dose of 400 mumol/kg body weight resulted in the inhibition of [3H]benzo(a)pyrene binding to epidermal DNA (48-73%) and protein (51-63%). The same dose of these plant phenols (400 mumol/kg) caused even greater inhibition of (+/-)-[3H]-7 beta,8 alpha-dihydroxy-7,8-dihydrobenzo(a)pyrene and [3H]-7,12-dimethybenz(a)anthracene binding to epidermal DNA and protein. The formation of (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene-deoxyguanosine adducts was substantially diminished in both epidermis (62-86%) and lungs (38-84%). These results indicate that tannic acid, quercetin, myricetin, and anthraflavic acid are potent inhibitors of carcinogen binding to epidermal and lung DNA and suggest that these plant phenols could prove useful in modifying the risk of tumor induction by PAHs such as benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene in these two tissues.

Animals↗
PubMed1987

Treatment of chronic postherpetic neuralgia with topical capsaicin. A preliminary study.

Continuing pain following herpes zoster is common in patients 60 years of age or older. Current treatments are generally unsatisfactory. The endogenous neuropeptide substance P is an important chemomediator of nociceptive impulses from the periphery to the central nervous system and has been demonstrated in high levels in sensory nerves supplying sites of chronic inflammation. In an attempt to alleviate the pain of 14 patients with postherpetic neuralgia, capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), known to deplete substance P, was applied topically to painful areas of skin for 4 weeks. Of the 12 patients completing this preliminary study, 9 (75%) experienced substantial relief of their pain. The only adverse reaction was an intermittent, localized burning sensation experienced by one patient with application of capsaicin. Although these results are preliminary, they suggest that topical application of capsaicin may provide a useful approach for alleviating postherpetic neuralgia and other syndromes characterized by severe localized pain.

Administration, Topical↗