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Biomedical subjects

D R Bickers

Publications and source records attributed to D R Bickers.

At least 127 records · Page 7Linked to original sources
PubMed1984

Clotrimazole, an inhibitor of epidermal benzo(a)pyrene metabolism and DNA binding and carcinogenicity of the hydrocarbon.

Clotrimazole, a topically applied imidazole antifungal agent widely used in dermatological practice, was shown to be a potent inhibitor of the epidermal metabolism of benzo(a)pyrene (BP) and its microsomal enzyme-mediated binding both to neonatal rat epidermal DNA in vivo and to calf thymus DNA in vitro. Varying concentrations of clotrimazole added to in vitro incubation systems resulted in a dose-dependent inhibition of cytochrome P-450-dependent microsomal aryl hydrocarbon hydroxylase (AHH) in control animals as well as in animals pretreated with topical application of known inducers of the enzyme. Inhibition of epidermal AHH by topically applied clotrimazole was time and dose dependent. The 50% inhibition of clotrimazole for epidermal AHH ranged from 0.12 to 0.25 microM, which suggests that clotrimazole is among the most potent inhibitors of epidermal AHH yet identified. Clotrimazole was also found to be a potent inhibitor of epoxide hydrolase activity in vitro with a 50% inhibition at 0.1 mM. High-pressure liquid chromatographic analysis of the metabolism of BP in rat epidermal microsomes revealed substantial inhibition of metabolite formation by clotrimazole. This occurred in microsomes prepared from untreated as well as animals pretreated with inducers of the enzyme. Furthermore, a single topical application of clotrimazole resulted in 80 and 30% induction of epidermal and hepatic glutathione S-transferase activity, respectively. Topical application of clotrimazole to the skin of BALB/c mice substantially increased the latent period for the development of skin tumors by 3-methylcholanthrene. These studies indicate that clotrimazole is an extremely potent inhibitor of epidermal BP metabolism and of the DNA-binding of polycyclic aromatic hydrocarbon (PAH) carcinogens, and is an enhancer of enzymes necessary for detoxification of the PAH. Clotrimazole also reduces the formation of carcinogenic and mutagenic metabolites of BP in vitro and in vivo and inhibits induction of skin tumors by the PAH. These data indicate that the imidazole antifungal clotrimazole offers promise as an agent useful for the modulation of PAH cancer risk in the skin.

Animals↗
PubMed1984

A comparative study of amcinonide and halcinonide in the treatment of eczematous dermatitis.

Thirty-three patients with acute or subacute eczematous dermatitis were treated for two weeks in a double-blind, parallel-group study to compare the efficacy and cosmetic acceptability of 0.1 percent amcinonide cream and 0.1 percent halcinonide cream. Patients in both treatment groups showed significant (p less than 0.05) improvement from baseline for most signs and symptoms at the three evaluation times (days 3, 7, and 14). Comparisons between groups showed no significant differences at any evaluation except at day 14, when the amicinonide-treated patients had significantly (p = 0.04) less edema. The physician's evaluations were not significantly different except at day 7, when the halcinonide patients showed significantly (p = 0.04) more overall improvement. The patients' overall evaluations were not significantly different at any time. In general, both creams were cosmetically acceptable. At day 3, seven amcinonide patients noted skin tightening compared to one halcinonide patient; four halcinonide patients (as well as two at day 7 and one at day 14) reported stinging compared to only one amcinonide patient. In addition, two halcinonide patients reported a burning sensation at one or more evaluations compared to no such reports from amcinonide patients. One other side effect, a metallic taste in the mouth, occurred in a halcinonide-treated patient.

Administration, Topical↗
PubMed1984

Psoralen pharmacology: studies on metabolism and enzyme induction.

Psoralens, tricyclic furocoumarins with potent photosensitizing properties in the skin, are now widely used in the treatment of several dermatologic diseases. In this study, the metabolism of 4,5',8-trimethylpsoralen (TMP) and 8-methoxypsoralen (8-MOP) was studied in mouse liver. Orally administered TMP is transformed into several metabolites, the major one of which is 4,8-dimethyl-5'-carboxypsoralen (DMCP) in both humans and mice. Orally administered 8-MOP is metabolized into at least 5 fluorescent moieties, including 8-hydroxypsoralen, the 4'5'-dihydro-diol of 8-MOP, and furocoumaric acid. The effects of 3 psoralens, 8-MOP, TMP, and isopsoralen (angelicin) on hepatic microsomal drug-metabolizing enzymes and cytochrome P-450 were assessed in mice and rats. Administered orally to CD-1 mice daily for 6 days, 8-MOP caused twofold to threefold increases in hepatic aryl hydrocarbon hydroxylase (AHH), ethylmorphine N-demethylase, and cytochrome P-450. The absorbance maximum of the induced cytochrome was at 450 nm. Aniline hydroxylase activity was unchanged. Chronic administration of 8-MOP to Skh:hairless-1 mice caused significant enhancement of hepatic ethylmorphine N-demethylase and cytochrome P-450 but had no effect on AHH, whereas chronically administered TMP had no significant effect on any of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Inhibition of epidermal metabolism and DNA-binding of benzo[a]pyrene by ellagic acid.

Ellagic acid, a common plant phenol, was shown to be a potent inhibitor of epidermal microsomal aryl hydrocarbon hydroxylase (AHH) activity in vitro, and of benzo[a]pyrene (BP)-binding to both calf thymus DNA in vitro and to epidermal DNA in vivo. The in vitro addition of ellagic acid (0.25-2.0 microM) resulted in a dose-dependent inhibition of AHH activity in epidermal microsomes prepared from control or carcinogen-treated animals. The I50 of ellagic acid for epidermal AHH was 1.0 microM making it the most potent inhibitor of epidermal AHH yet identified. In vitro addition of ellagic acid to microsomal suspensions prepared from control or coal tar-treated animals resulted in 90% inhibition of BP-binding to calf thymus DNA. Application of ellagic acid to the skin (0.5-10.0 mumol/10 gm body wt) caused a dose-dependent inhibition of BP-binding to epidermal DNA. Our results suggest that phenolic compounds such as ellagic acid may prove useful in modulating the risk of cutaneous cancer from environmental chemicals.

Animals↗
PubMed1983

Transition-state alkylation geometries of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene enantiomeric isomers with nucleic acid dimers.

The steric contact spaces associated with the reaction of the enantiomeric isomers of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (I) with the exocyclic amino group of guanine of dinucleoside dimer structures were examined for a fixed transition-state geometry. This reaction is sterically prohibited for the B form DNA conformation. If, however, the nucleic acid structure is deformed, such that the distance between two adjacent base pairs (one containing guanine and cytosine) is maximized, sterically allowed transition-state geometries can be identified. It was not possible to uniquely identify the preferred transition-state complex with respect to nucleic acid structure or isomer of I. However, two types of general transition-state geometries were observed. In one, I was located "outside" the nucleic acid structure; in the other geometry, I was intercalated between adjacent base pairs in the transition state. The intercalation process might serve as a physical catalyst for the alkylation of NH2-guanine by I.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1983

Intercalation of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene enantiomeric isomers with dinucleoside dimers: a basis for alkylation of the 2-amino group in guanine.

The minimum-energy intercalation-complex geometries of the (+/-)enantiomers of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (I) with two dinucleoside dimers were determined. The purpose of these calculations was to see if I could intercalate into DNA in such a way that the observed alkylation of the 2-amino group of guanine could occur subsequent to intercalation. For both dinucleoside dimer sequences, it was found that the (+)-(9 alpha, 10 alpha) isomer could form a stable intercalation complex in which the orientation and distance of the epoxide of I to the 2-amino group of guanine was close to the calculated critical transition-state geometry for the alkylation reaction. The (-)enantiomers can intercalate, but not in a manner close to the transition-state geometry necessary for the alkylation of the 2-amino group of guanine.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1983

Position paper--PUVA therapy. American Academy of Dermatology.

PUVA, the combination of psoralen (P) and long-wave ultraviolet radiation (UVA), is being used increasingly in the management of psoriasis and several other dermatologic disorders. While the acute toxicity of this modality, which includes erythema and blistering of the skin, can be avoided with careful monitoring of the dosimetry of the administered radiation, the potential chronic toxicity remains a source of concern. Since psoralens and UVA are clearly mutagenic, carcinogenic, cataractogenic, and may have as yet poorly understood effects on the immune system, it is imperative that all patients treated with this modality be carefully monitored for the development of neoplasia and cataracts. PUVA therapy should only be administered using specialized equipment that can be accurately monitored for its spectral irradiance by physicians thoroughly familiar with the risks and benefits of the modality.

Cataract↗
PubMed1983

Studies on the role of reactive oxygen species in mediating lipid peroxide formation in epidermal microsomes of rat skin.

The role of superoxide, hydrogen peroxide, and singlet oxygen in mediating nonenzymic and NADPH-supported enzymic lipid peroxidation in skin microsomes was investigated. Incubation of skin microsomes with NADPH and/or Fe+3-ADP or ascorbate resulted in the formation of lipid peroxides. The epidermis was the major target site for microsomal lipid peroxide formation in skin. Enzymic peroxidation of epidermal microsomes required NADPH and was oxygen-dependent. Addition of the nonenzymic catalysts, Fe+3 and ADP, to the enzymic peroxidation system had an additive effect on the generation of lipid peroxide in epidermal microsomes. Epidermal microsomal lipid peroxidation was inhibited by singlet oxygen quenchers such as dimethylfuran, histidine, and beta-carotene. Hydroxyl ion scavengers such as mannitol, benzoate, or ethyl alcohol and the enzymic scavenger of superoxide, superoxide dismutase, were all ineffective in this respect. Addition of EDTA, Mn+2, cytochrome c+3, and catalase to the NADPH-supported enzymic peroxidation system resulted in strong inhibition of lipid peroxide formation in skin. Glutathione or epidermal cytosol added alone or in combination to the NADPH-supported incubation system enhanced peroxidation of microsomal lipids. Vitamin E (alpha-tocopherol) inhibited lipid peroxidation. These results indicate that singlet oxygen may mediate lipid peroxide formation in epidermal microsomes.

Adenosine Diphosphate↗
PubMed1982

Evidence that coal tar is a mixed inducer of microsomal drug-metabolizing enzymes.

Topical application of coal tar (U.S.P.) to neonatal rats resulted in the induction of hepatic cytosolic glutathione-S-transferase and microsomal epoxide hydrolase and aminopyrine N-demethylase activities. Analogous to the effect of the polychlorinated biphenyl Aroclor 1254, treatment of neonatal rats with coal tar resulted in a one nm shift to the blue region in the wavelength maximum of the hepatic microsomal hemoprotein cytochrome P-450. These results demonstrate that therapeutic coal tar contains both type I and type II inducers of hepatic drug-metabolizing enzymes.

Animals↗
PubMed1982

The effect of psoralens on hepatic and cutaneous drug metabolizing enzymes and cytochrome P-450.

Psoralens are tricyclic furocoumarins with potent photosensitizing properties in the skin and are now widely used in the treatment of several dermatologic diseases. In this study the effect of 3 different psoralens 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP) and isopsoralen on hepatic microsomal drug-metabolizing enzymes and cytochrome P-450 has been assessed in mice and rats. 8-MOP administered orally to CD-1 mice daily for 6 days caused 2-3 fold increases in hepatic aryl hydrocarbon hydroxylase (AHH), ethylmorphine N-demethylase and cytochrome P-450. The absorbance maximum of the induced cytochrome was at 450 nm. Aniline hydroxylase activity was unchanged. Chronic administration of 8-MOP to hairless mice caused significant enhancement of hepatic ethylmorphine N-demethylase and cytochrome P-450 but had no effect on AHH; whereas chronically administered TMP had no significant effect on any of these parameters. Isopsoralen and TMP administered orally to CD-1 mice daily for 6 days had no effect on any of these liver enzymes or on hepatic P-450. 8-MOP administered daily for 6 days to rats caused a greater than 4-fold enhancement of AHH and greater than 2-fold enhancement of ethylmorphine N-demethylase and cytochrome P-450. These studies indicate that orally administered 8-MOP induces hepatic drug-metabolizing enzymes and cytochrome P-450 to a lesser extent than do the barbituates and suggest that this drug could influence the rate of biotransformation of concomitantly administered drugs in patients undergoing PUVA therapy.

Administration, Oral↗
PubMed1982

Induction of neonatal rat skin and liver aryl hydrocarbon hydroxylase by coal tar and its constituents.

Topical application of coal tar solution (USP) to neonatal rats resulted in the induction of skin and liver aryl hydrocarbon hydroxylase (AHH) activities. Furthermore indirect exposure of the animals to coal tar vapors resulted in induction of the enzyme in skin and liver. Cutaneous application of coal tar to pregnant rats resulted in induction of skin and liver AHH activity in both mothers and prenatal rats. Among several defined constituents of coal tar tested benzo(a)pyrene (BP), anthracene and acridine were found to have measurable induction effects on neonatal rat skin and liver AHH. These studies indicate that therapeutic coal tar solution as well as selected defined chemical constituents of coal tar are capable of altering the activity of AHH in skin and liver.

Acridines↗