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At least 847 records · Page 47Linked to original sources
PubMed2003

Influence of laminar flow on preorientation of coal tar pitch structural units: Raman microspectroscopic study.

In order to estimate the role of laminar flow of viscous, aromatic matter of carbonaceous precursor on microtextural preorientation in pregraphitization stage, we performed experiments with coal tar pitch (CTP). The principal hypothesis of preorientation of basic structural units (BSUs) in the case of laminar flow (pressure impregnation of CTP into porous matrix) and secondary release of volatiles during carbonization were studied. Glass microplates, planar porous medium with average distance between single microplates 5 microm were used as suitable porous matrix. Samples of CTP were carbonized up to 2500 degrees C. Optical microscopy reveals large flow domains in the sample of cokes carbonized between glass microplates. Raman microspectroscopy and high resolution transmission electron microscopy (HRTEM) show that at nanometric scale, the samples do not support the proposed hypotheses. With increasing temperature of pyrolysis, the graphitization of CTP impregnated into porous matrix proceeds to lower degree of structural ordering in comparison with single pyrolyzed CTP. This is explained by the release of volatile matter during carbonization in geometrically restricted spaces. More evident structural changes were discovered with the sample of single coke, where parts of fine grain mosaics, relicts of 'so called QI parts', reveal higher structural organization, in comparison with large and prolonged flow domains, similar to flow domains of cokes from microplates.

Coal Tar↗
PubMedDate not supplied

Damage to human alpha-1-proteinase inhibitor by aqueous cigarette tar extracts and the formation of methionine sulfoxide.

The effects of aqueous extracts of cigarette tar (ACT) on human alpha-1-proteinase inhibitor (alpha 1PI) are examined by determining alterations in the elastase inhibitory capacity (EIC), amino acid residue content, and electrophoretic behavior of the protein. Hydrogen peroxide generated in ACT by autoxidative processes accounts for the major portion of the loss of EIC. This is indicated by several lines of evidence, including the fact that anaerobic incubations of ACT with alpha 1PI cause negligible loss of EIC. The hydrogen peroxide content of the ACT was estimated by measuring the ability of the extracts to oxidize methionine to methionine sulfoxide; hydrogen peroxide concentrations that model those in ACT cause a similar loss in EIC. Exposure of alpha 1PI to ACT leads to methionine sulfoxide as the only detectable amino acid residue modification and explains the loss of EIC. This is the first report to directly demonstrate methionine sulfoxide formation in alpha 1PI exposed to cigarette smoke components in vitro. Similar amounts of methionine sulfoxide are found in alpha 1PI exposed to hydrogen peroxide at the concentrations predicted to be formed in ACT. Nondenaturing PAGE reveals that alpha 1PI exposed to ACT, but not hydrogen peroxide, shows changes in electrophoretic behavior; the changes are nonoxidative in nature and are not related to the loss of EIC. Studies on the effect of chelators on ACT-mediated damage to alpha 1PI indicate some role for metal ions; however, none of the chelators completely protect alpha 1PI.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed2005

Effect of a standardized complex mixture derived from coal tar on the metabolic activation of carcinogenic polycyclic aromatic hydrocarbons in human cells in culture.

A complex mixture of polycyclic aromatic hydrocarbons (PAH) extracted from coal tar, standard reference material (SRM) 1597, has been shown to initiate tumor formation in mouse initiation-promotion assays in our laboratory [(2001) Carcinogenesis 22 (7), 1077-1086]. To determine the effects of SRM 1597 on PAH activation in human cells, we investigated the PAH-DNA adduct formation in the human mammary carcinoma-derived cell line MCF-7. We examined the effects of SRM 1597 on the metabolic activation to DNA binding derivatives of two carcinogenic PAHs, the bay region containing benzo[a]pyrene (B[a]P) and the more carcinogenic fjord region containing dibenzo[a,l]pyrene (DB[a,l]P). PAH-DNA adduct analysis by 33P-postlabeling and reversed phase high-performance liquid chromatography revealed a significant decrease in the levels of both B[a]P and DB[a,l]P DNA adduct formation on cotreatment with SRM 1597 in comparison to cells exposed to B[a]P or DB[a,l]P alone. However, the inhibition of PAH-DNA adduct formation only occurred within the first 48 h of exposure in cells cotreated with SRM 1597 and B[a]P. In contrast, SRM 1597 significantly inhibited the level of DB[a,l]P DNA adducts throughout the 120 h of exposure. Induction of human cytochrome P450 (P450) enzymes 1A1 and P4501B1 on treatment with SRM 1597 was observed by immunoblots. These results suggest that the important factors in determining the carcinogenic activity of PAH within a complex mixture would depend on the ability of other components of the mixture to promote or inhibit the activation of carcinogenic PAH by the induction of P450 enzymes followed by the formation of DNA adducts.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Declining lung cancer mortality of young Australian women despite increased smoking is linked to reduced cigarette 'tar' yields.

Lung cancer data were examined to determine whether the mortality rates of young Australian women have continued to increase in line with the proportions of them who have smoked tobacco. Trends in annual age-specific lung cancer mortality were estimated for 1965-1998. Age-specific mortality rates and age-adjusted ratios of mortality rates were calculated for birth cohorts. Proportions of smokers in those cohorts were estimated from results of eight national surveys of smoking, and their mean ages of commencement and years of smoking were assessed from surveys of smokers in two states. Lung cancer mortality rates of 20-44-year-old Australian women peaked in 1986. Age-adjusted mortality rates are lower for women born in the 1950s and 1960s than for women born in the 1940s, despite higher proportions of smokers, younger age of commencement and longer duration of smoking by age 30 years in the more recent cohorts. Increased smoking has not resulted in higher lung cancer mortality for Australian women born in the 1950s and 1960s. Reductions in tar yields of Australian-made cigarettes, which would have affected primarily those born after the 1940s, may be responsible.

Adult↗
PubMed1986

Comparative characterization of organic emissions from diesel particles, coke oven mains, roofing tar vapors and cigarette smoke condensate.

This paper reports the characterization of the extractable organics from diesel particulate emissions compared to other complex organics which have been reported to increase the risk of human lung cancer. Class fractions of diesel, cigarette smoke condensate, roofing tar, and coke oven extracts were obtained using liquid/liquid partitioning and silica gel chromatography. Capillary GC/MS was used to identify compounds in each extract fraction. This manuscript reports the mass distribution after fractionation of each extract, all identified fraction components and quantification of selected mutagenic and carcinogenic compounds.

Air Pollutants↗
PubMed2006

Do reductions in the tar and nicotine yields of cigarettes help to explain recent reductions in lung cancer rates in young men and women in the United States?

Between 1985 and 2000, lung cancer rates in U.S. men and women aged 35-54 yr have declined. To investigate whether these declines can adequately be explained by changes in smoking prevalence, consumption, and duration, or if changes in tar and nicotine yields also contributed, two model-fitting approaches were used. Both approaches used individual person National Health Interview Survey data on smoking prevalence, age of starting and time of quitting, and national estimates of consumption per smoker and yields. Both approaches compared observed rates (by sex and age) relative to 1985, with those predicted after successively including various smoking variables into the model, making varying allowance for compensation for reduced yield. Approach A was simpler, based on mean smoking statistics estimated separately for current and former smokers. Approach B used the multistage model and individual smoking histories to estimate risk. Both approaches showed observed declines in risk were (except for men aged 35-39 yr) clearly greater than predicted based only on prevalence, consumption, and duration. Including yield generally improved the fit. At younger ages, models assuming substantial compensation (consistent with evidence from studies relating nicotine yield and intake) fitted well, but at age 50-54 yr in both sexes and age 45-49 yr in women, the decline was better fitted by models assuming little compensation. The conclusions were not sensitive to the precise parameter values assumed in the modeling. Interpretation is not straightforward, but the findings suggest declines in yields have contributed to the recent declines in rates in young U.S. men and women.

Adult↗
PubMedDate not supplied

Biomarkers of exposure and potential harm in adult smokers of 3-7 mg tar yield (Federal Trade Commission) cigarettes and in adult non-smokers.

The paper reports levels of 24-h urine nicotine and five of its major metabolites (expressed as nicotine-equivalents) and blood carboxyhaemoglobin as biomarkers of exposure to particulate- and gas-phase cigarette smoke, respectively, from an exploratory pilot study of adult smokers of 3.0-6.9 mg tar delivery (Federal Trade Commission (FTC) method) cigarettes. On multiple occasions over 6 weeks, blood high-sensitivity C-reactive protein (hs-CRP), fibrinogen, HDL- and LDL-cholesterol, and 24-h urine 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) and 11-dehydro-thromboxane B2 (11-dehydro-TxB2) were also evaluated as biomarkers of potential harm. All the biomarkers examined, except for LDL-cholesterol, discriminated with high sensitivity and specificity between adult smokers and non-smokers overall. Except for HDL-cholesterol, all biomarker medians were greater in adult smokers than in non-smokers: urine nicotine-equivalents 64.514 versus < 0.034 nmol mg-1 creatinine (p<0.001), carboxyhaemoglobin 4.0 versus 0.4% saturation (p<0.001), hs-CRP 0.27 versus 0.12 mg dl-1 (p=0.05), fibrinogen 292 versus 248 mg dl-1 (p<0.001), HDL-cholesterol 46 versus 53 mg dl-1 (p=0.003), LDL-cholesterol 119 versus 109 mg dl-1 (p=0.18), urine 8-epi-PGF2alpha 1935 versus 1034 pg mg-1 creatinine (p<0.001) and urine 11-dehydro-TxB2 973 versus 710 pg mg-1 creatinine (p<0.001). All the biomarkers of exposure and most of the biomarkers of potential harm showed no time of sampling (by visit week) effect.

Biomarkers↗
PubMed1983

Estimating the hazards of "less hazardous" cigarettes. III. A study of the effect of various smoking conditions on yields of hydrogen cyanide and cigarette tar.

A brand of cigarette with nominal tar and nicotine yields of 4.0 mg and 0.4 mg, respectively, was examined under various machine-smoked conditions that reflect the wide range of human smoking behavior. Three levels of each of five smoking parameters--butt length, puff duration, puff interval, puff volume, and ventilation occlusion--were examined, and the effects on puff number and total particulate matter (TPM) as well as gas phase, particulate phase, and total HCN yields were estimated. Yields of hydrogen cyanide (a ciliatoxic agent) and TPM varied significantly under different smoking conditions. Ventilation occlusion had the most pronounced effect, accounting for 34% of the response variation of TPM yields and 42% of the response variation for total hydrogen cyanide yields. In the survey of available brands, total hydrogen cyanide yields varied from 2 to 233 micrograms/cigarette for the 115 brands tested, a range less than that observed for a single brand smoked under various nonstandard conditions, providing a possible explanation for the previously noted lack of correspondence between HCN yields under standard conditions and levels of thiocyanate in samples of smokers' plasma and saliva. In addition, hydrogen cyanide yields and efficiency of filters in removing HCN were examined under standard smoking conditions. Acetate filters, the most common variety, were found to remove an average of about 14% of the hydrogen cyanide from the mainstream smoke.

Analysis of Variance↗
PubMed1995

Potentiation of 2,6-dinitrotoluene genotoxicity in Fischer 344 rats by pretreatment with coal tar creosote.

Pretreatment of male Fischer 344 rats for 5 wk with coal tar creosote, a coal distillation product that is widely used as a wood preservative, potentiated the excretion of urinary mutagens in 2,6-dinitrotoluene (DNT) treated rats. Creosote increased the bioactivation of DNT to significantly greater levels of urinary genotoxic metabolites and/or formed DNA adducts in the liver. A significant increase in the excretion of mutagenic DNT metabolites was observed after the first week of creosote treatment, peaked at wk 3, and then decreased by 33% after 5 wk of treatment. Nevertheless, there was a significant increase (66%) in the formation of DNT-derived DNA adducts in the livers of rats treated with DNT plus creosote at wk 5. Increased cecal beta-glucuronidase activity and reduced small intestinal nitroreductase activity may play roles in the bioactivation of DNT. The excretion of mutagenic DNT metabolites supplies useful information about the bioactivation of DNT; it does not provide a useful index of DNT-derived hepatic DNA adduct formation. Such interactions could be important to predictive risk assessment because the overall cancer risk of such chemical mixtures may exceed the sum of the component risks.

Analysis of Variance↗
PubMed1992

Coal tar therapy does not influence in vitro benzo[a]pyrene metabolism and DNA adduct formation in peripheral blood lymphocytes of psoriatic patients.

Human lymphocytes (HL) from healthy subjects and psoriatic patients were treated in vitro for 24 h with 4 microM [3H]benzo[a]pyrene (B[a]P) and 2 microM (-)-B[a]P-7,8-dihydrodiol in order to verify if the coal tar (CT) used in the therapy of psoriasis, which is characterized by a high content of polycyclic aromatic hydrocarbons (PAH), influences the formation of B[a]P-DNA adducts and the metabolism of B[a]P. Significant amounts of syn-BPDE-dGuo adducts were detected in all the examined HL samples, but no significant difference in the amounts of total BPDE-DNA adducts or of specific anti- and syn-BPDE-dGuo adducts was observed between healthy subjects and psoriatic patients, or between psoriatic patients before and after CT treatment. Moreover, the CT treatment of psoriatic patients did not influence the enantiomeric composition of B[a]P-7,8-dihydrodiols present in the HL culture medium, among which the (-)-7R,8R form was found to predominate (greater than 98%) in all the HL samples. The existence in HL of a specific metabolic pathway of B[a]P leading to the formation of (-)-syn-BPDE and the corresponding tetrols, through the epoxidation of the (-)-7R,8R enantiomer of B[a]P-7,8-dihydrodiol, was confirmed by determining the tetrols derived from the syn- and anti-stereoisomers of BPDE, released in HL culture medium after treatment for 24 h with 2 microM (-)-B[a]P-7,8-dihydrodiol. Although B[a]P-7,10/8,9 and B[a]P-7/8,9,10 tetrols, derived from (+)-anti-BPDE, were the predominant isomers, significant amounts of B[a]P-7,9/8,10 and B[a]P-7,9,10/8 tetrols, derived from the hydrolysis of (-)-syn-BPDE, were also detected. The mean ratio of anti/syn tetrols in healthy subjects was significantly lower than in psoriatic patients, but no difference in that ratio was found in psoriatic patients before and after CT treatment.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1985

Mutagenic activity and polycyclic aromatic hydrocarbon levels in urine of workers exposed to coal tar pitch volatiles in an anode plant.

The mutagenicity of urinary extracts and the excretion of PAH from workers occupationally exposed to coal tar pitch volatiles in an anode plant were analyzed. Mutagenicity of the urinary extracts was measured by means of the plate test using S. typhimurium strain TA 98. After concentration, hydrolysis and reduction of the urine samples, PAH levels were measured by high resolution gas chromatography/mass spectrometry. No significant difference was found in the mutagenicity of the urinary extracts of non-smokers occupationally exposed to PAH as compared with the controls. Low PAH concentrations were found in the urine of the exposed subjects, which lends further support to the negative results obtained with the Ames' test. The increase of urinary PAH excretion, in relation to occupational exposure, was mainly due to the less mutagenic, low molecular weight compounds.

Air Pollutants, Occupational↗
PubMedDate not supplied

Effects of varied smoking machine parameters on deliveries of total particulate matter and selected smoke constituents from an ultra low-tar cigarette.

A typical ultra low-tar cigarette was mechanically smoked under varying conditions designed to simulate potential changes in human smoking behavior. Determination of the yields of total particulate matter and analyses of individual smoke components, including nicotine, phenolics, acids, and the humectant, glycerol, demonstrated significant changes in smoke composition as related to intensity and frequency of inhalation. Physical obstruction of tipping paper ventilation, by negating the effects of air dilution of smoke, resulted in increased smoke deliveries similar to those observed when puffing volume and frequency were increased.

Chromatography, Gas↗
PubMed2000

Bioavailability of the genotoxic components in coal tar contaminated soils in Fischer 344 rats.

The effect of chemical aging on the bioavailability and subsequent genotoxicity of coal tar (CT)-contaminated soils was evaluated in a 17-day feeding study using Fischer 344 male rats. Rats consumed a control diet or diets amended with soil, 0.35% CT, or soil freshly prepared or aged for 9 months with 0.35% CT. Mild treatment-related microscopic lesions in liver tissue and elevated enzyme levels in serum were detected in all CT treatment groups. The (32)P-postlabeling assay was employed to determine DNA adduct formation in treated animals. All CT treatment groups induced DNA adducts in both the liver and lung. Adduct levels were 3-fold higher in lung DNA compared to hepatic DNA. After correcting adduct levels for total ingested polycyclic aromatic hydrocarbons (PAHs), a significant decrease (p < 0.05) in adduct levels was observed in both CT/soil treatment groups compared to CT control in liver and lung DNA. Adduct profiles of (32)P-postlabeled hepatic and lung DNA displayed several nonpolar DNA adducts that comigrated with PAH-adducted calf thymus DNA standards as determined through both thin-layer chromatography (TLC) and high-pressure liquid chromatography (HPLC). These results suggest that soil, but not aging of contaminants in soil, decreases the bioavailability of genotoxic components in CT, as evidenced by DNA adduct analysis.

Animals↗
PubMed2001

Inhibition of human cytochrome P450 2E1 by nicotine, cotinine, and aqueous cigarette tar extract in vitro.

Cigarette smoke is a complex mixture containing, among other chemicals, pyridine alkaloids and N-nitrosamines. Carcinogenic tobacco-specific N-nitrosamines, N-nitrosodimethylamine (NDMA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are both activated by cytochrome P450 (CYP) 2E1 in rats. Previous reports indicate that nicotine and the main nicotine metabolite, cotinine, reduce the mutagenicity of both NNK and NDMA in Salmonella typhimurium. To study the mechanism of this effect, we examined inhibition of CYP 2E1 activity, as assessed by p-nitrophenol (pNP) hydroxylation, by nicotine, cotinine, and an aqueous cigarette tar extract (ACTE) in human 2E1-expressing microsomes. At all substrate concentrations (0-1.25 mM) nicotine was a significantly more potent inhibitor of CYP 2E1 activity compared to cotinine. Estimated Ki values for nicotine and cotinine (both at 10 mM) were 13 mM (2 mg/ml) and 308 mM (54 mg/ml) respectively. The Ki for ACTE was 0.2 mg/ml at a concentration of 0.32 mg/ml. This rank order for inhibition was also seen when the data was expressed as IC(50). When compared on a mass/vol basis, ACTE was a significantly more potent CYP 2E1 inhibitor relative to nicotine and cotinine. Double-reciprocal plots indicated that nicotine and ACTE inhibited by a competitive, while cotinine inhibited CYP 2E1 by an uncompetitive mechanism. Although the contribution of nicotine to ACTE-mediated 2E1 inhibition is probably modest, pyridine alkaloid-mediated CYP 2E1 inhibition is a possible mechanism for the observed inhibition of NNK and NDMA mutagenicity by nicotine and cotinine in vitro.

Cotinine↗
PubMed1999

Gordonia alkanivorans sp. nov., isolated from tar-contaminated soil.

Twelve bacterial strains isolated from tar-contaminated soil were subjected to a polyphasic taxonomic study. The strains possessed meso-diaminopimelic acid as the diagnostic diamino acid of the peptidoglycan, MK-9(H2) as the predominant menaquinone, long-chain mycolic acids of the Gordonia-type, straight-chain saturated and monounsaturated fatty acids, and considerable amounts of tuberculostearic acid. The G + C content of the DNA was 68 mol%. Chemotaxonomic and physiological properties and 16S rDNA sequence comparison results indicated that these strains represent a new species of the genus Gordonia. Because of the ability of these strains to use alkanes as a carbon source, the name Gordonia alkanivorans is proposed. The type strain of Gordonia alkanivorans sp. nov. is strain HKI 0136T (= DSM 44369T).

Actinomycetales↗
PubMed1989

Monoclonal antibodies directed characterization of epidermal and hepatic cytochrome P-450 isozymes induced by skin application of therapeutic crude coal tar.

A single application of crude coal tar (CCT) solution (USP) to the skin of neonatal rats was shown to induce epidermal and hepatic cytochrome P-450(P-450)-dependent monooxygenase activities. To further characterize the induction response, in this study we have utilized highly specific monoclonal antibodies (MoAb) 1-7-1, 2-66-3, and 1-98-1 directed against highly purified rat liver P-450s induced by 3-methyl-cholanthrene, phenobarbital and ethanol, respectively. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of hepatic microsomes prepared from CCT-treated animals showed a significant increase in the coomassie blue stainable proteins in the P-450 region; however, this was not evident in epidermal microsomes. Immunoblot analysis of epidermal and hepatic microsomes with MoAb 1-7-1 revealed strong immunoprecipitin bands in both tissues. MoAb 2-66-3 showed significant immunoreactivity only with hepatic microsomes. Interestingly, CCT treatment resulted in suppression of immunoreactivity with MoAb 1-98-1 in hepatic microsomes. MoAb 1-7-1 and 2-66-3 exhibited concentration-dependent inhibitory effects in aryl hydrocarbon hydroxylase and 7-ethoxycoumarin-O-deethylase activities induced by CCT application. MoAb 1-7-1 was substantially more effective in this respect. Epidermal and hepatic microsomes prepared from CCT-treated rats showed significantly greater metabolism of benzo(a)pyrene (BP). MoAb 1-7-1 and MoAb 2-66-3 inhibited BP metabolism in both the tissues. However, MoAb 1-7-1 was more inhibitory in this regard as compared to MoAb 2-66-3. These studies indicate that topical application of therapeutic CCT to the skin of neonatal rats results in induction of P-450 isozyme c in epidermis and isozymes b and c in liver, and that this induction is associated with the suppression of P-450 isozyme j in liver.

Administration, Topical↗
PubMed1987

Human hair follicle benzo[a]pyrene and benzo[a]pyrene 7,8-diol metabolism: effect of exposure to a coal tar-containing shampoo.

Assay systems for the evaluation of carcinogen interaction with human tissues are essential for assessing cancer risk. Hair follicles are a readily available source of human epithelial tissue and offer an excellent system with which to study carcinogen metabolism in human populations. In this study freshly plucked human hair follicles were employed to measure the metabolism of benzo[a]pyrene (BP), benzo[a]pyrene-7,8-diol (BP 7,8-diol), and the enzyme-mediated binding of [3H]-BP to DNA. The effect of human exposure to a crude coal tar (CCT)-containing shampoo, a preparation rich in polycyclic aromatic hydrocarbons (PAHs), on these parameters was also evaluated. Twelve healthy volunteers were studied before and after shampooing their hair daily for 4 days with the CCT-containing shampoo. Wide interindividual variation was observed in basal cytochrome P-450-dependent aryl hydrocarbon hydroxylase (AHH) activity which ranged from 0.6-17.6 fmol water-soluble BP metabolites/h/hair follicle (mean +/- SE of 32 individuals was 9.7 +/- 0.9). After use of the shampoo for 4 days AHH activity increased in 10 of the 12 volunteers (50-148%) and enhancement of enzyme-mediated binding of BP to DNA was detected in most subjects. Hair follicles were shown to convert BP to several metabolic species including BP 7,8-diol, a major precursor of the ultimate carcinogenic metabolite of BP. Benzo[a]pyrene-7,8-diol itself was also metabolized by the human hair follicles in this system. Clotrimazole, a known inhibitor of the metabolism of BP as well as the carcinogenicity of the hydrocarbon in rodent skin, was found to inhibit AHH and the in vitro metabolism of BP and BP 7,8-diol in human hair follicles. Oral administration of a similar antifungal imidazole, ketoconazole at a dose of 200 mg daily for 5 days, to healthy volunteers also resulted in greater than 90% inhibition of hair follicle AHH activity. These studies indicate that hair follicles represent an accessible tissue suitable for assessing the extent of PAH carcinogen metabolism in human subjects. Furthermore, enzyme activity critical to cancer induction by PAHs was shown to be inducible following the use of a CCT-containing shampoo. This carcinogen-activating enzyme system was substantially inhibited by imidazole compounds, suggesting that they may prove effective as anticarcinogens in human populations.

Aryl Hydrocarbon Hydroxylases↗
PubMed1986

Additive effects of ultraviolet B and crude coal tar on cutaneous carcinogen metabolism: possible relevance to the tumorigenicity of the Goeckerman regimen.

The effect of cutaneous exposure to ultraviolet B (UVB) radiation alone, to crude coal tar (CCT) alone, and to the combination of UVB and CCT on the inducibility of the microsomal cytochrome P-450-dependent carcinogen-metabolizing enzyme aryl hydrocarbon hydroxylase (AHH) and other monooxygenases such as 7-ethoxyresorufin O-deethylase (ERD) and 7-ethoxycoumarin O-deethylase (ECD) activities in the skin of neonatal rats was studied. Exposure of the animals to UVB (400-1600 mJ/cm2) alone resulted in a dose-dependent increase in cutaneous enzyme activities. At a UVB dose of 1200 mJ/cm2 increases in AHH, ECD, and ERD were 194%, 115%, and 244%, respectively. A single topical application of CCT (10 ml/kg) 24 h before sacrifice resulted in significant induction of AHH (350%), ECD (921%), and ERD (796%) activities. Treatment of animals with the same dose of CCT followed by UVB exposure resulted in additive and/or synergistic effects on AHH (858%), ECD (1229%), and ERD (1166%) activities in the skin. In contrast, exposure of animals to UVB prior to CCT application had effects no different from those of CCT alone. Epoxide hydrolase and glutathione S-transferase activities in skin from all experimental groups were not different from those of controls. High-pressure liquid chromatographic analysis of the metabolism of benzo[a]pyrene (BP) by cutaneous microsomes prepared from animals treated with UVB alone, CCT alone, and the combination of UVB and CCT revealed increased formation of all the metabolites in each experimental group. The largest increase in metabolite formation occurred in animals receiving CCT followed by UVB exposure. The inducibility of trans-7,8-diol formation by UVB alone and CCT alone was 203% and 435%, respectively, whereas with CCT followed by UVB it was 1065%. The differential responses in AHH activity were found to parallel the capacity of skin microsomal enzymes to enhance the binding of [3H]-BP to DNA. These studies indicate that the sequence of exposure to the components of the Goeckerman regimen in rodents greatly influences metabolic activity in skin. When applied in the same sequence employed in the Goeckerman regimen (CCT followed by UVB exposure) the additive effect upon catalytic activity essential for cancer initiation suggests a possible mechanism for the enhancement of human skin cancer in individuals exposed to this therapeutic regimen.

Animals↗