Biomedical subjects

D R Bickers

Publications and source records attributed to D R Bickers.

171 records · Page 10Linked to original sources

PubMedDate not supplied

Carbohydrate metabolism in porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) has a known increased incidence of diabetes mellitus and hepatic involvement. We investigated glucose tolerance and glucoregulatory hormone alterations in seven patients with PCT and correlated these results with hepatic histology by percutaneous liver biopsy. Abnormal glucose tolerance was observed in six of the seven patients (87%). Fasting serum insulin levels were normal range, and normal glucose and growth hormone responses to standard, exogenous intravenous insulin were observed. Fasting serum glucagon and urine free cortisol levels were normal in those patients in whom they were measured. While varying degrees of abnormalities were found on histopathologic exam of the liver biopsies, no patient met the criteria for cirrhosis, and none of the patients demonstrated abnormal levels of insulin counterregulatory hormones commonly seen in cirrhosis. Thus, liver disease may not be the sole cause of the observed glucose intolerance and hyperinsulinemia in PCT patients.

Adult↗

PubMedDate not supplied

Induction of CYP1A1 mRNA in rat epidermis and cultured human epidermal keratinocytes by benz(a)anthracene and beta-naphthoflavone.

Cytochrome P-4501A1 (CYP1A1) plays a major role in the bioactivation of procarcinogens in target tissues, including skin. However, the factors controlling CYP1A1 expression in mammalian skin are unknown. Utilizing the reverse transcriptase-linked polymerase chain reaction, we analyzed the effect of treatment with beta-naphthoflavone (beta-NF) and benz(a)anthracene on the expression of CYP1A1 mRNA in rat epidermis and normal human epidermal keratinocytes (NHEK). Inducer treatment of rats and NHEKs resulted in several-fold increases in aryl hydrocarbon hydroxylase activity. Following inducer treatment of adult or neonatal rats, increase in CYP1A1 gene message occurred as compared with that in controls. Higher basal level and inducibility were detected in mature rather than in 4-day-old rats. This induction occurred as early as 4 hr after beta-NF application. Exposure to beta-NF and benz(a)anthracene also resulted in substantial increases in gene message in NHEK. Northern blot analyses complemented the polymerase chain reaction data. These results indicate that CYP1A1 gene expression is increased in mammalian epidermis by inducers of epidermal aryl hydrocarbon hydroxylase activity.

Animals↗

PubMedDate not supplied

Isozyme-specific monoclonal antibody-directed assessment of induction of hepatic cytochrome p-450 by clotrimazole.

Clotrimazole, an N-substituted imidazole widely used as an antifungal agent, has been shown to both inhibit and induce hepatic cytochrome P-450 and related monooxygenase activities. In this study the profile of hepatic cytochrome P-450 isozyme(s) induced by clotrimazole treatment of male Sprague-Dawley rats was investigated. Clotrimazole administration (100 mg/kg, daily for 4 days, ig) resulted in 86% induction of spectrally detectable cytochrome P-450 in hepatic microsomes. In these microsomes 7-ethoxycoumarin O-deethylase (126%), aminopyrine N-demethylase (176%), benzphetamine N-demethylase (117%), p-nitrophenol hydroxylase (89%), and 7-ethoxyresorufin O-deethylase (62%) activities were significantly induced, whereas aryl hydrocarbon hydroxylase activity remained unchanged. Characterization of cytochrome P-450 isozyme(s) in hepatic microsomes prepared from clotrimazole-treated animals was based on the immunoreactivity of these microsomes with highly specific monoclonal antibodies (MAbs) raised against 3-methylcholanthrene-specific P-450 (MAb 1-7-1), phenobarbital-specific P-450 (MAb 2-66-3), pregnenolone-16 alpha-carbonitrile-specific P-450 (MAb C2), and ethanol-inducible P-450 (MAb 1-98-1). Western blot analysis of hepatic microsomes prepared from clotrimazole-treated animals with MAb 2-66-3, MAb 1-98-1, and MAb C2 revealed strong immunoreactive bands, whereas moderate reactivity was observed with MAb 1-7-1. MAb 2-66-3 significantly inhibited 7-ethoxycoumarin O-deethylase activity 45%), whereas MAb 1-7-1 moderately inhibited 7-ethoxyresorufin O-deethylase activity (-30%) in clotrimazole-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Capsaicin as an in vitro inhibitor of benzo(a)pyrene metabolism and its DNA binding in human and murine keratinocytes.

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the active principle of capsicum fruits, such as hot peppers, is a known inhibitor of substance P. This substance was also found to be a potent in vitro inhibitor of human and murine epidermal metabolism of benzo(a)pyrene (BP) and the enzyme-mediated binding of BP metabolites to DNA. In both untreated and 3-methylcholanthrene-treated neonatal rat epidermal microsomes, capsaicin resulted in a dose-dependent inhibition of aryl hydrocarbon hydroxylase activity with an I50 value of 3.0 X 10(-4)-3.6 X 10(-4) M. A Lineweaver-Burk plot of the inhibition of aryl hydrocarbon hydroxylase activity suggested that the inhibition is of the noncompetitive type with Ki value of 50 microM. Capsaicin also inhibited BP metabolism and the binding of 3H-BP to DNA in BALB/c mouse and human keratinocytes. The formation of BP-7,8-diol was also substantially diminished in both systems in the presence of capsaicin (180-300 microM). Our results indicate that the substance P inhibitor, capsaicin, is also an inhibitor of epidermal BP metabolism and DNA binding of its metabolites. Therefore, in addition to its neurological effects, capsaicin may represent a new category of compound with anti-carcinogenic effects.

Animals↗

PubMedDate not supplied

Epidermis: the major site of cutaneous benzo(a)pyrene and benzo(a)pyrene 7,8-diol metabolism in neonatal BALB/c mice.

The metabolism of benzo(a)pyrene (BP) and benzo(a)pyrene-7,8-diol (BP-7,8-diol) by microsomes prepared from whole skin, dermis, and epidermis of neonatal BALB/c mice pretreated with topically applied 3-methylcholanthrene (MCA) was compared. In control animals, microsomes prepared from epidermis showed higher rates of metabolism of BP and BP-7,8-diol (1.4-2.6-fold) than did microsomes prepared from whole skin or dermis. A single topical application of MCA increased the rate of metabolism of BP and BP-7,8-diol in microsomes prepared from whole skin, dermis, and epidermis. The greatest increase occurred in the epidermis. The in vivo covalent binding of [3H]BP, [3H]BP-7,8-diol, and 7,12-[3H]dimethylbenz(a)anthracene ([3H]DMBA) to DNA was found to be greater in epidermis (8.7-15.4-fold) than in whole skin or in dermis. A single topical application of MCA to BALB/c mice enhanced the in vivo binding of [3H]BP, [3H]BP-7,8-diol and [3H]DMBA to DNA of whole skin, dermis, and epidermis more than 2-fold. Exposure of Salmonella tester strains TA98 and TA100 to 2-aminoanthracene, a skin carcinogen, in the presence of an epidermal metabolic activation mixture resulted in a greater mutagenic response when compared to activation mixtures derived from whole skin or dermis. These results indicate that epidermis is the major site of polycyclic aromatic hydrocarbon metabolism and of enzyme-mediated covalent binding of polycyclic aromatic hydrocarbon carcinogens to DNA in skin of BALB/c mice and that topically applied MCA has maximum enzyme induction effects in this skin compartment.

Animals↗

PubMedDate not supplied

Interaction of epicatechins derived from green tea with rat hepatic cytochrome P-450.

Green tea has been used for generations in China and Asia as an antipyretic and diuretic. Prior studies have shown that extracts of green tea inhibit the mutagenicity of polycyclic aromatic hydrocarbons and aflatoxin B1. In this study, we investigated the interaction of certain flavonoid components of green tea epicatechin derivatives including (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), and (-)-epigallocatechin-3-gallate (EGCG) with rat hepatic microsomal cytochrome P-450 (P-450). The addition of EC, EGC, ECG, and EGCG to hepatic microsomes prepared from phenobarbital (PB)-treated rats resulted in spectral changes characterized by absorbance maxima at 420 nm and minima at 380 nm, typical of modified Type II (reverse Type I) binding. Of the epicatechin derivatives, EGCG and ECG showed greater spectral change with oxidized P-450 and time- and concentration-dependent inhibition of the binding of carbon monoxide to dithionite-reduced cytochrome P-450. The addition of EC, EGC, ECG, and EGCG to microsomes prepared from control, PB- or 3-methylcholanthrene-treated rats resulted in a dose-dependent inhibition of cytochrome P-450-dependent aryl hydrocarbon hydroxylase, 7-ethoxycoumarin O-deethylase, and 7-ethoxyresorufin O-deethylase activities. EGCG was the most potent in this regard. Green tea polyphenols and epicatechin derivatives also significantly inhibited NADPH-cytochrome c reductase activity. An examination of the structure activity relationship of epicatechin derivatives suggests that the inhibitory effect on the microsomal enzyme system may be due to the galloyl groups or hydroxyl groups on the molecule. Our data indicate that these extracts of green tea may have potential as anticarcinogens.

Animals↗

PubMedDate not supplied

Drug metabolism in skin. Comparative activity of the mixed-function oxidases, epoxide hydratase, and glutathione S-transferase in liver and skin of the neonatal rat.

Aryl hydrocarbon hydroxylase (AHH) activity in the skin of neonatal rats was compared to that in epidermis, dermis, and other body tissues. Following topical application of benzo[a]pyrene (BP) or the polychlorinated biphenyl mixture Aroclor 1254 there was induction of AHH in each tissue studied. There was a greater increase in the activity of skin enzyme as compared to other extrahepatic tissues. When whole-organ activity (pmol of 3-OH-BP per min per whole organ) was considered, skin represented 2%, 21%, and 27% or whole body activity in control, BP-treated, and Aroclor 1254-treated animals, respectively. Skin microsomes from control rats exhibited 2, 0.5, 24, and 6% of corresponding liver microsomal AHH, 7-ethoxycoumarin de-ethylase, NADPH-cytochrome c reductase, and epoxide hydratase activities, respectively. Glutathione S-transferase activity in skin cytosol was 15% of the corresponding hepatic activity. Following topical application of Aroclor 1254 there were increases in the activity of AHH and 7-ethoxycoumarin de-ethylase in the skin and the liver. Glutathione S-transferase (40-60%) and epoxide hydratase (83-94%) activities in neonatal rat liver were induced by skin application of Aroclor 1254.

7-Alkoxycoumarin O-Dealkylase↗

PubMedDate not supplied

Age-related changes in benzo(a)pyrene metabolism and epoxide-metabolizing enzyme activities in rat skin.

The postnatal development of microsomal aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECD), epoxide hydrolase (EH) [benzo(a)pyrene (BP)-4,5-oxide as substrate], and cytosolic glutathione S-transferase (GST) was studied in skin of Sprague-Dawley rats. Animals were treated with skin application of 3-methylcholanthrene (MCA) (40 mg/kg, 24 hr before sacrifice) or acetone. Enzyme activities were detected in animals of all ages. AHH and ECD in control rats showed slight age-dependent variation. Age-dependent differences in inducibility of skin AHH and ECD by topically applied MCA were observed. At 4, 6, 10, 18, 24, 32, and 55 days of age, the inducibility of AHH was 11, 18, 18, 19, 20, 23, and 21-fold, respectively. A similar pattern was observed for ECD. EH activity in 24-day-old skin was twice that in 4-day-old animals. GST activity remained constant throughout maturation. EH and GST activities were not altered by MCA. BP metabolism was studied in control and MCA-induced neonatal (4-day-old), young (18-day-old), and adult (55-day-old) animals. MCA treatment increased the rate of metabolism of BP at all ages studied. Higher rates of BP metabolism occurred in adult skin as compared to younger or neonatal rat skin. Inducibility of trans-7,8-diol formation by topically applied MCA was highest in the adult (19-fold) rat skin as compared to younger (12-fold) or neonatal rat skin (10-fold). These studies suggest that xenobiotic metabolism in skin of rats undergoes variable changes during aging which could exert some influence on pharmacologic responses to topically applied agents in cutaneous tissue.

Aging↗

PubMedDate not supplied

A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia.

A large double-blind, vehicle-controlled study of 143 patients with chronic postherpetic neuralgia (PHN) was performed to evaluate the degree of efficacy of topically applied capsaicin 0.075% cream. In addition, the safety and efficacy of long-term application of topical capsaicin in PHN was assessed by following patients in an open-label study for up to 2 years. In the double-blind phase, 143 patients with PHN of 6 months' duration or longer were enrolled. Since epidemiologic studies of patients who receive no treatment have shown that only 10% to 25% of those with PHN after 1 month will still have pain at 1 year, two separate efficacy analyses were performed: one with all evaluable patients (n = 131) and the other with 93 patients whose PHN lasted for longer than 12 months prior to study startup. All efficacy variables, including the physician's global evaluation of reduction in PHN pain, changes in pain severity on the categoric scale, visual analogue scale for pain severity, visual analogue scale for pain relief, and functional capacity scale, showed significant improvement at nearly all time points throughout the study for both patient groups, based on duration of PHN pain. In contrast, the group receiving vehicle cream remained essentially unchanged. Data from the long-term, open-label phase (up to 2 years, n = 77), which immediately followed the 6-week blinded phase, showed that the clinical benefit in patients treated for a short (6-week) period with topical capsaicin could be maintained or amplified in most patients (86%) during prolonged therapy. There were no serious adverse effects observed or reported throughout the trial; in fact, the only side effect associated with capsaicin treatment was the burning or stinging at local sites of application (in 9% of patients) during exposures of up to 2 years (long-term phase). On the basis of these data, we conclude that capsaicin 0.075% cream is a safe and effective treatment for the pain of postherpetic neuralgia and should be considered for initial management of patients with this condition.

Administration, Topical↗