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PubMed2003

Comparative metabolism of chrysene and 5-methylchrysene by rat and rainbow trout liver microsomes.

We have investigated the metabolism of chrysene (CHR) and 5-methychyrsene (5-MeCHR) by Shasta rainbow trout (Oncorhyncus mykiss) and Long Evans rat liver microsomes to assess the effect of a non-benzo ring methyl substituent on the reactions involved in the metabolism of polycyclic aromatic hydrocarbons (PAHs). Trout as well as rat liver microsomes metabolized both CHR and 5-MeCHR at essentially similar rates, indicating that the methyl substituent does not alter the substrate specificity of the cytochrome P450(s) involved in the metabolism of the two PAHs. Dihydrodiols were the major CHR metabolites formed by both trout and rat liver microsomes, whereas the trout liver microsomes formed a considerably higher proportion of 5-MeCHR phenols compared to diols, indicating that 5-methyl substitution alters the substrate specificity of trout microsomal epoxide hydrolase for 5-MeCHR epoxides. Unlike trout liver microsomes, rat liver microsomes formed a much greater proportion of 5-MeCHR diols compared to 5-MeCHR phenols, suggesting that 5-MeCHR epoxides are better substrates for the microsomal epoxide hydrolase present in rat liver than for the enzyme in trout liver. Both trout and rat liver microsomes are more efficient at attacking the bay-region bond versus the non-bay-region double bond in chrysene. In contrast the reverse is true in the case of 5-MeCHR, indicating that a non-benzo ring methyl substituent alters the regioselectivity of the enzymes involved in the oxidative metabolism of PAHs.

Animals↗
PubMedDate not supplied

Effect of phenobarbital and chrysene on theophylline elimination determined by noncompartmental analysis.

The elimination of intravenously administered theophylline was determined in rats after oral pretreatment with phenobarbital and chrysene. The pharmacokinetic parameters of theophylline (Cl, Vdss, MRT) were determined by a noncompartmental method (the moment analysis). The enzyme inducers increased the theophylline clearance from 0.157 l/kg/h in control to 0.232 l/kg/h after chrysene and 0.266 l/kg/h after phenobarbital pretreatment.

Animals↗
PubMed1982

Mutagenicity of the optical isomers of the diastereomeric bay-region chrysene 1,3-diol-3,4-epoxides in bacterial and mammalian cells.

The mutagenic activities of the four optically pure (+)- and (-)-enantiomers of the two diastereomeric bay-region chrysene 1,2-diol-3,4-epoxides were evaluated in histidine-dependent strains of Salmonella typhimurium and in cultured Chinese hamster V79 cells. In strain TA98 of S. typhimurium, (-)-1 alpha, 2 beta-dihydroxy-3 beta, 4 beta-epoxy-1,2,3,4-tetrahydrochrysene was 5 to 10 times more active than the other three optical isomers. However, in strain TA100 of S. typhimurium and in Chinese hamster V79 cells, (+)-1 beta, 2 alpha-dihydroxy-3 alpha, 4 alpha-epoxy-1,2,3,4-tetrahydrochrysene was the most mutagenic diol-epoxide and was from 5 to 40 times more active than the other three optical isomers. The bay-region (+)- and (-)-3,4-epoxy-1,2,3,4-tetrahydrochrysene isomers has identical mutagenic activities in all three systems. These studies indicate that the presence and orientation of the hydroxyl groups play an important role in modulating the mutagenic activity of bay-region epoxides of chrysene in both bacterial and mammalian cells.

Animals↗
PubMed1981

Quantum chemical studies of methyl and fluoro analogs of chrysene: metabolic activation and correlation with carcinogenic activity.

Specific electronic properties related to metabolic transformation and adduct formation by DNA were calculated for a series of methyl, dimethyl and n-fluoro-5-methyl derivatives of chrysene with the aim of identifying molecular properties which could be used as reliable indicators of their relative carcinogenic behavior. Using the semiempirical all valence electron IEHT method, the bay region bonds of 5MC were found to have enhanced nucleophilic reactivity to epoxide formation relative to chrysene. In addition, in one of the nonequivalent bay regions, the 1, 2, 3, 4 region, the distal (1, 2) bond was found to be more reactive than the proximal (3, 4) bond. This reactivity pattern leads to an easily formed diol epoxide carbocation, the postulated ultimate carcinogen. By contrast, in the other (7, 8, 9, 10) bay region, the proximal (9, 10) bond is the more reactive, suggesting formation of the "wrong," i.e., less stable diol epoxide carbocation. Consistent with earlier studies of other PAH, calculations by the INDO method of the ease of carbon cation formation from a bay region diol epoxide yielded a set of values which gave a good correlation with carcinogenicity.

Animals↗
PubMed2002

Practical synthesis of an open geodesic polyarene with a fullerene-type 6:6-double bond at the center: diindeno[1,2,3,4-defg;1',2',3',4'-mnop]chrysene.

Diindeno[1,2,3,4-defg;1',2',3',4'-mnop]chrysene (1), the smallest possible alkene-centered C60 substructure with a curved pi-system, is obtained in 25-35% yield by flash vacuum pyrolysis of the twisted 1,1'-dibromobifluorenylidene (2) on a 100 mg scale at 1050 degrees C. At 1200 degrees C, the bowl-shaped hydrocarbon 1 rearranges to the planar isomer diindeno[5,6,7,1-defg;5',6',7',1'-lmnop]chrysene (14) by a double 5/6 ring-expansion/ring-contraction. X-ray crystallography establishes that the central carbon atoms of 1 are nearly 80% as pyramidalized as the carbon atoms of C60 (POAV angles = 9.0 degrees and 11.6 degrees for 1 and C60, respectively). A four-step synthesis has been developed to prepare the pyrolysis precursor (2) as a mixture of (E)- and (Z)-isomers in 39% overall yield from commercially available 9-fluorenone-1-carboxylic acid (10).

Journal Article↗
PubMed1991

Micronuclei in mouse skin cells following in vivo exposure to benzo[a]pyrene, 7,12-dimethylbenz[a]anthracene, chrysene, pyrene and urethane.

Detection of micronuclei (MN) in skin cells from HRA/Skh hairless mice treated with chemical or physical agents may prove informative in qualitative and quantitative studies of skin carcinogenesis. MN induction and cell survival were estimated in cytokinesis-blocked keratinocytes, cultured for 4 days in vitro, after a single topical dose of various organic compounds. Treatment with 2.56 micrograms (10 nmol) 7,12-dimethylbenz[a] anthracene (DMBA) resulted in maximal MN induction in cells removed from skin 12-24 hr after topical administration (79-88 MN/1,000 cells compared with 10-16 MN/1,000 cells in acetone-treated controls). Even in cells removed only 1 hr after DMBA treatment, a significant increase in MN was evident. However, to allow sufficient time for metabolic activation, a sampling time for of 24 hr was adopted for all test substances. Dose-dependent increases in MN were observed with DMBA, benzo[a]pyrene, chrysene, and urethane. Increased numbers of micronucleated cells were detected at the lowest doses administered in the present study (0.128, 0.5, 50, and 50 micrograms, respectively). Although reduced cell recovery occurred following exposure of mice to acetone, pyrene, and other chemicals, there was no evidence that cytotoxicity contributed to MN scored in keratinocytes. Moreover, the probable noncarcinogen, pyrene, failed to induce MN at doses from 2.5 micrograms to 2.5 mg/mouse. These results show that it is possible to assess chemical exposure in skin by measuring cell survival and skin genotoxicity by measuring MN induction in cultured keratinocytes. The available data suggest that MN induction may be a useful indicator of the carcinogenic potential of chemicals applied to the skin.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Activating mutations in human c-Ha-ras-1 protooncogene induced by stereoisomeric fjord-region benzo[c]chrysene diol-epoxides.

The mutagenicity of fjord-region benzo[c]chrysene diol-epoxide (BcCDE) stereoisomers((+) anti-BcCDE, (-)anti-BcCDE, (+)syn-BcCDE, and (-)syn-BcCDE) was studied in a forward-mutation system. pEC plasmid containing the human c-Ha-ras-1 proto-oncogene was reacted in vitro with each optically active isomer separately and transfected into NIH/3T3 cells. Morphologically transformed foci were cloned, and DNA obtained from these foci was tested for the presence of Ha-ras-1 sequence by Southern blot analysis. A total of 50 transformed foci (11-14 for each diastereomer) were generated. To determine the nature of mutations responsible for activating the proto-oncogene, regions of the gene likely to contain the activating mutations were amplified by polymerase chain reaction and then subjected to hybridization with specific oligonucleotides. Gene mutations in 42 of 50 transformed foci were characterized by these methods, and most were found at codon 61 (27), followed by codons 12 (13) and 13 (two). All mutations observed were either G --> T or A --> A --> T transversions. Thirty-six were G --> T transversion mutations occurring at codons 61, 12, and 13. The remaining six were A --> T transversions at codon 61.BcCDE stereoisomers may specifically attack guanine and adenine and result in the mutations observed. Some differences in codon preference but not in the types of mutations were found among these optically active isomers.

3T3 Cells↗
PubMed1997

Mechanism of differential catalytic efficiency of two polymorphic forms of human glutathione S-transferase P1-1 in the glutathione conjugation of carcinogenic diol epoxide of chrysene.

The kinetics of the conjugation of glutathione (GSH) with anti-1, 2-dihydroxy-3,4-oxy-1,2,3,4-tetrahydrochrysene (anti-CDE), the activated form of the widespread environmental pollutant chrysene, catalyzed by two naturally occurring polymorphic forms of the pi class human GSH S-transferase (hGSTP1-1), has been investigated. The polymorphic forms of hGSTP1-1, which differ in their primary structure by a single amino acid in position 104, exhibited preference for the GSH conjugation of (+)-anti-CDE, which is a far more potent carcinogen than (-)-anti-CDE. When concentration of anti-CDE was varied (5-200 microM and the GSH concentration was kept constant at 2 mM, both hGSTP1-1(I104) and hGSTP1-1(V104) obeyed Michaelis-Menten kinetics. However, the Vmax of GSH conjugation of anti-CDE was approximately 5.3-fold higher for the V104 variant than for the I104 form. Calculation of catalytic efficiency (kcat/Km) thus resulted in a value for hGSTP1-1(V104), 28 mM-1 s-1, that was 7.0-fold higher than that for hGSTP1-1(I104), 4 mM-1 s-1. The mechanism of the differences in the kinetic properties of hGSTP1-1 isoforms toward anti-CDE was investigated by molecular modeling of the two proteins with GSH conjugation products in their active sites. These studies revealed that the enantioselectivity of hGSTP1-1 for (+)-anti-CDE and the differential catalytic efficiencies of the V104 and I104 forms of hGSTP1-1 in the GSH conjugation of (+)-anti-CDE were due to the differences in the active-site architecture of the two proteins. The results of the present study, for the first time, provide evidence for the toxicological relevance of GSTP1-1 polymorphism in humans and suggest that the population polymorphism of hGSTP1-1 variants with disparate enzyme activities may, at least in part, account for the differential susceptibility of individuals to environmental carcinogens such as anti-CDE and possibly other similar carcinogens.

Animals↗
PubMed2006

Polycyclic aromatic hydrocarbon (PAH) metabolizing enzyme activities in human lung, and their inducibility by exposure to naphthalene, phenanthrene, pyrene, chrysene, and benzo(a)pyrene as shown in the rat lung and liver.

In order to survey changes and activities in the polycyclic aromatic hydrocarbon (PAH)-metabolizing enzymes implicated in lung cancer susceptibility studies, we investigated enzyme induction by 2-5-ring-sized 'biomarker' PAHs in rat liver and lung, and the activities in five human lung specimens. Naphthalene, phenanthrene, pyrene, chrysene, and benzo[a]pyrene (BaP) were administered to rats for 3 days (25-128 mg/kg/day) and the responses compared with those of model inducers. PAH treatment increased the CYP1A-catalyzed activity of pyrene 1-hydroxylation and 7-ethoxyresorufin O-deethylation in rat liver by up to 28- and 279-fold, and in rat lung by up to 22- and 51-fold, respectively. 1-Naphthol (hUGT1A6), 1-hydroxypyrene (hUGT1A6/1A9), and entacapone (hUGT1A9) are markers of PAH-glucuronidating human uridine diphosphate-glucuronosyltransferases (UGT). These activities increased up to 6.4-fold in rat liver and up to 1.9-fold in rat lung. NADPH:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase activities increased up to 5.3- and 1.6-fold (liver), and up to 4.4- and 1.4-fold (lung), respectively. CYP1A showed the best liver-to-lung relationship (R (2 )=( )0.90). The inducing efficiency by PAHs differed extensively: control 60-fold), many times greater than the experimental (inducible/constitutive) variation in the rat. Kinetics of 1-hydroxypyrene glucuronidation showed two low-K (m) forms both in rat and human lung. Since the 2-4-ring PAHs (major constituents) were poor enzyme inducers, it appears that the PAH-metabolizing pathways are mainly induced by BaP-type minor constituents. Gene-environmental interactions which magnify polymorphic variability in pulmonary bioactivation/detoxification capacity probably play a key role in individual susceptibility to (or protection against) chemically induced lung cancer. Hence, human exposure to PAH mixtures with high content of BaP-type hydrocarbons confers a potentially higher health risk than PAH mixtures with low content of procarcinogens.

Animals↗
PubMed1989

Sulphotransferase-mediated activation of the carcinogen 5-hydroxymethyl-chrysene. Species and sex differences in tissue distribution of the enzyme activity and a possible participation of hydroxysteroid sulphotransferases.

Sulphation of the carcinogen 5-hydroxymethyl-chrysene (5-HCR) to the active metabolite 5-HCR sulphate occurred at significant rates in all of hepatic cytosols prepared from the male and female experimental animals, rats, mice, guinea-pigs and hamsters. The 5-HCR-sulphating activity was also found in kidney cytosols of all the experimental animals used, while their activities were much less than those of hepatic cytosols. In the male mice, the enzyme activity of testis was higher than any other examined tissue. Small intestine and adrenal of male and female guinea-pigs had relatively high enzyme activities. Small enzyme activities were also found in a variety of extrahepatic tissues of some of these animals. Marked species and sex differences (female much greater than male in the rat and mouse) were observed in the hepatic enzyme activity. In the female rat liver which showed the highest 5-HCR-sulphating activity among the examined tissues of all the animals, a typical hydroxysteroid sulphotransferase inhibitor, dehydroepiandrosterone (DHA) sulphate (1 mM), potently and competitively inhibited the sulphation of 5-HCR as well as that of DHA, a typical substrate for hydroxysteroid sulphotransferases. On the contrary, the phenol sulphotransferase inhibitors, pentachlorophenol and 2,6-dichloro-4-nitrophenol, had only a little effect on these enzyme activities even at a concentration of 50 microM that showed a potent inhibition of the phenol sulphotransferase activity. These results suggest that 5-HCR be sulphated in the female rat liver by hydroxysteroid sulphotransferases, but not by phenol sulphotransferases.

Animals↗
PubMed1995

Conjugation of anti-dihydrodiol epoxides of benzo[a]pyrene, chrysene, benzo[c]phenanthrene and dibenz[a,h]anthracene with glutathione catalyzed by cytosol and by the Mu-class glutathione transferase HTP II from rat liver.

The (+/-)-anti-dihydrodiol epoxides (DE) of benzo[a]pyrene (BP), chrysene (Chr), benzo[c]phenanthrene (BcPh) and dibenz[a,h]anthracene (DBA) were incubated in the presence of glutathione (GSH) with hepatic cytosol from untreated and Aroclor 1254 pretreated rats and with the Mu-class glutathione transferase (GST) HTP II from rat liver. The diastereoisomeric GSH conjugates formed were separated, identified and quantified by HPLC employing synthetic reference compounds. All (+/-)-anti-dihydrodiol epoxides investigated in this study were proven to be substrates of the cytosolic GSTs. The highly mutagenic and carcinogenic (+)-anti-DE with R,S,S,R absolute configuration was preferentially conjugated in the case of BP and Chr. Aroclor 1254 pretreatment increased the turnover 2-3-fold and changed the enantioselectivity. The previously purified GST HTP II exhibited a high degree of enantioselectivity (> or = 95%) towards the R,S,S,R-configurated enantiomer in the case of the bay-region (+/-)-anti-BPDE, (+/-)-anti-ChrDE and (+/-)-anti-DBADE, whereas in the case of fjord-region (+/-)-anti-BcPhDE both enantiomers were good substrates. The contribution of HTP II to the enzymatic activity of the cytosolic GST pool was estimated to be in the range of 11-32%. In agreement with previous results, the observed enantioselectivity of the purified enzyme seems to be of minor significance considering the total GST pool in the liver.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1990

Comparative tumor initiating activities of cyclopentano and methyl derivatives of 5-methylchrysene and chrysene.

Previous studies showed that 5,6-dimethylchrysene (5,6-diMeC) and 5,7-diMec were significantly less tumorigenic than 5-methylchrysene (5-MeC). These results were unexpected based on the known mechanism of metabolic activation of 5-MeC and indicated the presence of critical steric requirements for tumorigenicity at the 6 and 7 positions of 5-MeC. In this study, the structure activity relationships were further extended by comparing the tumor-initiating activities on mouse skin of 5-MeC, 6,7-cyclopentano-5-MeC, 5,6-diMeC, 6,7-diMeC, 5,7-diMeC, chrysene and 6,7-cyclopentanochrysene. 5-MeC was the most tumorigenic compound, with activity significantly higher than all other compounds tested. Among the other compounds. Only 5,6-diMeC was significantly tumorigenic. The results demonstrate that substitution of methyl or methylene groups at the 6 or 7 positions of 5-MeC leads to a significant reduction of tumor initiating activity.

Animals↗
PubMed1991

Comparative tumorigenicity in newborn mice of chrysene- and 5-alkylchrysene-1,2-diol-3,4-epoxides.

We determined the tumorigenicity in newborn mice of racemic anti-1,2-diol-3,4-epoxides of chrysene, 5-methylchrysene, 5-ethylchrysene and 5-propylchrysene. Among the four diol epoxides, only anti-5-methylchrysene-1,2-diol-3,4-epoxide was highly tumorigenic. It was 15-30 times more potent in induction of pulmonary tumors than the other compounds. The results demonstrate that molecular shape is critical in determining the tumorigenic activity of alkylchrysene diol epoxides. A methyl group in the same bay region as the epoxide ring leads to exceptional activity. This may be a consequence of DNA adduct conformation.

Adenoma↗
PubMed1983

Comparative kinetics of benz(a)anthracene, chrysene and triphenylene in rats after oral administration. I. Study with single compounds.

Distribution and elimination of benz(a)anthracene (B(a)A), chrysene (Ch), and triphenylene (Tr) were compared after oral administration of the single compounds to 7-8-week-old female rats. These four-ring isomers were chosen because of their different carcinogenicity. The compounds have high affinity for lipid-rich tissues such as brain, mammary and parametrial adipose tissue. The relative availability of these compounds in the tissues examined decreased in the order Tr greater than B(a)A greater than Ch, but fecal elimination diminished in the opposite order Ch greater than B(a)A greater than Tr. Availability and fecal elimination of single polycyclic aromatic hydrocarbons (PAH) were influenced by the dose and concentration of PAH in the vehicle.

Administration, Oral↗
PubMedDate not supplied

Effect of fasting, induction, sex and age on clearance of benz(a)anthracene and chrysene by isolated perfused rat liver.

Hepatic clearances of benz(a)anthracene (B(a)A) and chrysene (Ch) by isolated perfused liver of female rats were similar when measured with hydrocarbons singly (B(a)A 4.3 ml/min, Ch 5.1 ml/min) or in a mixture (4.7 resp. 5.3 ml/min). Clearance of both isomers by livers from 24 h fasted donors was approximately halved. In vivo pretreatment with B(a)A (22.8 mg per kg for 2 days) significantly increased elimination of both hydrocarbons. Hepatic clearance of B(a)A was significantly higher in male rats than in females of the same age (8 weeks). Elimination of both hydrocarbons was significantly lower in 2 year-old males.

Aging↗
PubMed1984

Comparative kinetics of oral benz(a)anthracene, chrysene and triphenylene in rats: study with hydrocarbon mixtures.

Distribution and elimination of benz(a)anthracene (B(a)A) was compared in blood, liver, brain, parametrial adipose and mammary tissue of young female rats after oral administration of the polycyclic aromatic hydrocarbons (PAH) singly or in equimolar mixtures with chrysene (Ch) or triphenylene (Tr). The relative availability of B(a)A in tissues was not influenced by Ch or Tr in the mixture. However, the presence of B(a)A halved the relative availability of Tr and raised that of Ch. The relative availability of the three isomers decreased in the order Tr greater than B(a)A greater than Ch; this may be correlated to their solubility in water.

Adipose Tissue↗
PubMed1987

Reversed-phase high-performance liquid chromatographic separation of phenolic derivatives of benzo[a]pyrene, benz[a]anthracene, and chrysene with monomeric and polymeric C18 columns.

The separation of monohydroxylated derivatives (phenols) of benzo[a]pyrene, benz[a]anthracene, and chrysene was studied by reversed-phase high-performance liquid chromatography using a monomeric Zorbax ODS column and a polymeric Vydac C18 column. The Vydac C18 column resolved the phenols of each hydrocarbon with a wide range of retention times than the Zorbax ODS column. Four K-region phenols of benzo[a]pyrene are either not separated or marginally separated on both monomeric and polymeric columns. Other K-region and non-K-region phenols of all three hydrocarbons can be separated by using the monomeric and polymeric columns in combination.

Animals↗
PubMed1986

Direct separation of non-K-region mono-ol and diol enantiomers of phenanthrene, benz[a]anthracene, and chrysene by high-performance liquid chromatography with chiral stationary phases.

The direct separation of 26 bay region and non-bay region mono-ol and diol enantiomers of phenanthrene, benz[a]anthracene, and chrysene was compared by high-performance liquid chromatography on commercially available columns, packed with gamma-aminopropylsilanized silica to which either (R)-N-(3,5-dinitrobenzoyl)phenylglycine(R-DNBPG) or (S)-N-(3,5-dinitrobenzoyl)leucine(S-DNBL) was either ionically or covalently bonded. In general, enantiomers of bay region mono-ols and diols are more efficiently resolved than those of non-bay region derivatives. Elution orders of enantiomers on either chiral stationary phase are the same, regardless of whether the chiral stationary phase is ionically or covalently bonded. Except for the enantiomers of 4-hydroxy-4-methyl-1,2,3,4-tetrahydrobenz[a]anthracene, 1,2,3,4-tetrahydrobenz[a]anthracene trans-1,2-diol, and benz[a]anthracene trans-1,2-dihydrodiol, elution orders of resolved enantiomers on R-DNBPG are reversed on S-DNBL. The enantiomers are generally more efficiently resolved on R-DNBPG than on S-DNBL. With the exception of the elution order of the enantiomeric 4-hydroxy-1,2,3,4-tetrahydrochrysene, the results of this study are consistent with the chiral recognition mechanisms proposed by Pirkle and co-workers, who developed the chiral stationary phases used in this study.

Benz(a)Anthracenes↗