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D M Jerina

Publications and source records attributed to D M Jerina.

At least 19 recordsLinked to original sources
PubMed1992

Mutagenic specificities of four stereoisomeric benzo[c]phenanthrene dihydrodiol epoxides.

The pS189 shuttle vector carrying a supF target gene was used to compare the mutagenic specificities of the four configurational isomers of benzo[c]phenanthrene 3,4-dihydrodiol 1,2-epoxide. One of these isomers is the most tumorigenic dihydrodiol epoxide tested to date and another is essentially inactive as a tumorigen. Overall mutagenicities were not correlated with tumorigenicities, but each configurational isomer induced a unique spectrum of mutational hot spots in the supF target gene, which monitors primarily point mutations. It is suggested that the demonstrated isomer-specific selectivity for mutation targets within the supF gene may be indicative of a similar selectivity for one gene versus another and that such selectivity may be one determinant of relative tumorigenicity.

Base Sequence↗
PubMed1992

High selectivity of polyclonal antibodies against DNA modified by diastereomeric benzo[c]phenanthrene-3,4-diol-1,2-epoxides.

Polyclonal antibodies were developed in New Zealand White rabbits against DNA modified with diastereomeric benzo[c]phenanthrene-3,4-diol-1,2-epoxide (B[c]PhDE)-1 (4-hydroxyl and epoxide cis) and B[c]PhDE-2 (4-hydroxyl and epoxide trans). Antiserum developed against B[c]PhDE-2-DNA was stereoselective. In competitive ELISA assays using wells coated with 160 fmol B[c]PhDE-2-DNA adducts, B[c]PhDE-2-DNA gave 50% inhibition at 200 fmol adducts/well. B[c]PhDE-1-DNA required a 10-fold higher amount of adducts/well to give 50% inhibition. Benzo[a]pyrene-7,8-diol-9,10-epoxide-2-DNA and 7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide-1-DNA caused only a 30% inhibition even at the highest doses tested (greater than 4000 fmol adducts/well). For antiserum developed against B[c]PhDE-1-DNA, 50% inhibition required 570 fmol B[c]PhDE-1-DNA adducts in wells coated with 100 fmol B[c]PhDE-1-DNA adducts. 7,12-Dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide-1-DNA and B[c]PhDE-2-DNA were also effective competitors: they caused 50% inhibition at 1900 and 1800 fmol adducts/well respectively. In contrast, benzo[a]pyrene-7,8-diol-9,10-epoxide-2-DNA gave no inhibition at the highest dose of competitor tested (4050 fmol adducts/well). Antisera from three rabbits immunized with B[c]PhDE-2-DNA demonstrated similar antigen specificities. The properties of these antisera differ from those reported previously for antibodies developed against benzo[a]pyrene-DNA in that they show selectivity for DNA modified by specific hydrocarbon diolepoxides, in one case for B[c]PhDE-2-DNA and in the other for B[c]PhDE-DNA or 7,12-dimethylbenz[a]anthracene-3,4-diol-1,2-epoxide-1-DNA. The specificity of these antisera will facilitate analysis of the modification of DNA by different polycyclic aromatic hydrocarbon diolepoxides.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1991

Dose-dependent differences in the profile of mutations induced by an ultimate carcinogen from benzo[a]pyrene.

Mutations in the coding region of the hypoxanthine (guanine) phosphoribosyltransferase (HPRT) gene of Chinese hamster V-79 cells were examined after exposure of the cells to a high cytotoxic dose (0.48 microM; 35% survival) and a low noncytotoxic dose (0.04 microM; 100% survival) of the ultimate carcinogen (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-BPDE]. Independent 8-azaguanine-resistant colonies were isolated and cDNAs were prepared by reverse transcription. The coding region of the cDNA of the HPRT gene was amplified by the polymerase chain reaction and sequenced. An examination of the DNA base sequence changes induced by different doses of (+)-BPDE demonstrated that the high dose of (+)-BPDE caused base substitution mutations almost exclusively at G.C base pairs whereas the low dose of (+)-BPDE caused mutations at both G.C and A.T base pairs. Thus, use of a low dose of (+)-BPDE allowed the detection of mutations (at A.T base pairs) that were not readily observed with a high dose of (+)-BPDE. The data also suggest that the low dose of (+)-BPDE may have caused a different profile of base substitutions at G.C base pairs and exon deletions than the high dose. The results indicate dose-dependent differences in the profile of mutations for an ultimate carcinogen.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1991

Autoprocessing of the HIV-1 protease using purified wild-type and mutated fusion proteins expressed at high levels in Escherichia coli.

Various constructs of the human immunodeficiency virus, type 1 (HIV-1) protease containing flanking Pol region sequences were expressed as fusion proteins with the maltose-binding protein of the malE gene of Escherichia coli. The full-length fusion proteins did not exhibit self-processing in E. coli, thereby allowing rapid purification by affinity chromatography on cross-linked amylose columns. Denaturation of the fusion protein in 5 M urea, followed by renaturation, resulted in efficient site-specific autoprocessing to release the 11-kDa protease. Rapid purification involving two column steps gave an HIV-1 protease preparations of greater than 95% purity (specific activity approximately 8500 pmol.min-1.micrograms protease-1) with an overall yield of about 1 mg/l culture. Incubation of an inactive mutant protease fusion protein with the purified wild-type protease resulted in specific trans cleavage and release of the mutant protease. Analysis of products of the HIV-1 fusion proteins containing mutations at either the N- or the C-terminal protease cleavage sites indicated that blocking one of the cleavage sites influences the cleavage at the non-mutated site. Such mutated full-length and truncated protease fusion proteins possess very low levels of proteolytic activity (approximately 5 pmol.min-1.micrograms protein-1).

ATP-Binding Cassette Transporters↗
PubMed1991

Continuous microspectrophotometric measurement of DNA polymerase activity: application to the Klenow fragment of Escherichia coli DNA polymerase I and human immunodeficiency virus type 1 reverse transcriptase.

Progress of DNA- and/or RNA-directed DNA polymerization reactions can be measured continuously using circular dichroism (CD) or ultraviolet (UV) spectroscopy. In the presence of the Klenow fragment of Escherichia coli DNA polymerase I, a CD change of -0.27 +/- 0.06 millidegree at 248 nm and a UV change of -2.7 +/- 0.3 milliabsorbance units at 275 nm occur upon incorporation of 120 pmol of dTMP in a reaction volume of 120 microliters (1 microM dTMP incorporation) into a synthetic template-primer, p(dA)40-60.p(dT)20. The transcription of poly(A).p(dT)12-18 by reverse transcriptases can also be monitored using these methods. Kinetic parameters for the polymerization reaction catalyzed by the Klenow fragment were determined from initial velocity measurements using CD or UV assays and were in close agreement with those measured by the standard single point radiochemical filtration assay. The generality of optical techniques for the measurement of DNA polymerase activity was shown by the use of a partially self-complementary hairpin-shaped oligonucleotide substrate for the Klenow fragment. Addition of a single nucleotide residue under steady-state conditions to this 35-mer at a concentration of 1.5-3 microM gave an easily measurable absorbance decrease at 275 nm, and the absorbance changes upon sequential addition of nucleotide units were additive.

Base Sequence↗
PubMed1991

Covalent bonding of bay-region diol epoxides to nucleic acids.

Although the solution chemistry of diol epoxides is now fairly well understood, a great deal remains to be elucidated regarding their reaction in the presence of DNA. Not only DNA but also small molecules are capable of sequestering diol epoxides in aqueous solutions with equilibrium constants on the order of 10(2)-10(4) M-1. In the case of DNA, at least two major families of complexes are presently recognized, possibly the result of groove binding vs. intercalation. As is the case for diol epoxides free in solution, the complexed diol epoxides undergo solvolysis to tetraols and in some cases possibly to keto diols as well. Fractionation between covalent bonding and solvolysis from within the complex(s) is determined more by the nature of the parent hydrocarbon from which the diol epoxide is derived than any other factor. Studies of a wide variety of alkylating and arylating agents have show that practically every potentially nucleophilic site on DNA can serve as a target for modification. In the case of the diol epoxides, practically all of the modification occurs at the exocyclic amino groups of the purine bases. In contrast to the diol epoxides, other epoxides such as those derived from aflatoxin B1, vinyl chloride, propylene, 9-vinylanthracene, and styrene preferentially bind to the aromatic ring nitrogens N-7 in guanine and N-3 in adenine (cf. Chadha et al., 1989). Molecular modeling as well as the spectroscopic evidence suggests that the hydrocarbon portion of the diol epoxides lies in the minor groove of DNA when bound to the exocyclic 2-amino group of guanine and in the major groove when bound to the exocyclic 6-amino group of adenine. Detailed conformational analysis of adducted DNA should prove to be extremely valuable in developing mechanistic models for the enzymatic processing of chemically altered DNA. At present, the critical lesion or lesions responsible for induction of neoplasia remains obscured by the large number of apparently noncritical adducts which form when polycyclic hydrocarbon diol epoxides bond to DNA.

Animals↗
PubMed1991

Novel stereoselectivity of rat liver cytochrome(s) P450 toward enantiomers of the trans-1,2-dihydrodiol of triphenylene.

Metabolism of 3H-labeled (+)-(S,S)- and (-)-(R,R)-1,2-dihydrodiols of triphenylene by rat liver microsomes and 11 purified isozymes of cytochrome P450 in a reconstituted monooxygenase system has been examined. Although both enantiomers were metabolized at comparable rates, the distribution of metabolites between phenolic dihydrodiols and bay-region, 1,2-diol 3,4-epoxide diastereomers varied substantially with the different systems. Treatment of rats with phenobarbital (PB) or 3-methylcholanthrene (MC) caused a slight reduction or less than a twofold increase, respectively, in the rate of total metabolism (per nanomole of cytochrome P450) of the enantiomeric dihydrodiols compared to microsomes from control rats. Among the 11 isozymes of cytochrome P450 tested, only cytochromes P450c (P450IA1) and P450d (P450IA2) had significant catalytic activity. With either enantiomer of triphenylene 1,2-dihydrodiol, both purified cytochrome P450c (P450IA1) and liver microsomes from MC-treated rats formed diol epoxides and phenolic dihydrodiols in approximately equal amounts. Purifed cytochrome P450d (P450IA2), however, formed bay-region diol epoxides and phenolic dihydrodiols in an 80:20 ratio. Interestingly, liver microsomes from control or PB-treated rats produced only diol epoxides and little or no phenolic dihydrodiols. The diol epoxide diastereomers differ in that the epoxide oxygen is either cis (diol epoxide-1) or trans (diol epoxide-2) to the benzylic 1-hydroxyl group. With either purified cytochromes P450 (isozymes c or d) or liver microsomes from MC-treated rats, diol epoxide-2 is favored over diol epoxide-1 by at least 4:1 when the (-)-enantiomer is the substrate, while diol epoxide-1 is favored by at least 5:1 when the (+)- enantiomer is the substrate. In contrast, with liver microsomes from control or PB-treated rats, formation of diol epoxide-1 relative to diol epoxide-2 was favored by at least 2:1 regardless of the substrate enantiomer metabolized. This is the first instance where the ratio of diol epoxide-1/diol epoxide-2 metabolites is independent of the dihydrodiol enantiomer metabolized. Experiments with antibodies indicate that a large percentage of the metabolism by microsomes from control and PB-treated rats is catalyzed by cytochrome P450p (P450IIIA1), resulting in the altered stereoselectivity of these microsomes compared to that of the liver microsomes from MC-treated rats.

Animals↗
PubMed1989

Mutagenicity of dihydrodiols and diol epoxides of dibenz[a, h]acridine in bacterial and mammalian cells.

Bay-region diol epoxides are ultimate carcinogenic metabolites of a number of polycyclic aromatic compounds. Dibenz[a, h]acridine can form two diastereomeric pairs of these diol epoxides which are not positionally equivalent as a result of the nitrogen atom at position 7. We have assessed the structure-activity relationships resulting from heterocyclic nitrogen substitution by examining the mutagenic activity of these four bay-region diol epoxides of dibenz[a,h]acridine in both bacterial and mammalian cells. In strains TA98 and TA100 of Salmonella typhimurium, the diastereomeric 10,11-diol-8,9-epoxides were 20 to 40 times more mutagenic than the corresponding 3,4-diol-1,2-epoxides. Furthermore, in strain TA100, dibenz[a,h]acridine 10,11-dihydrodiol, the expected metabolic precursor of the 10,11-diol-8,9-epoxide, was metabolically activated by rat hepatic microsomes up to a 12-fold greater extent than the 3,4-dihydrodiol. In Chinese hamster V79 cells, the 10,11-diol-8,9-epoxide diastereomers were 20 to 80 times more mutagenic than their 3,4-diol-1,2-epoxide counterparts. Quantum mechanical calculations of the predicted ease of benzylic carbocation formation at C-1 and C-8 from the diol epoxides indicate that the 3,4-diol-1,2-epoxides should be less reactive due to resonance destabilization of the C-1 carbocation as a result of the electronegative nitrogen atom. Decreased chemical reactivity of 3,4-diol-1,2-epoxides may explain their decreased mutagenic activity.

Acridines↗
PubMed1989

Continuous spectrophotometric assay for retroviral proteases of HIV-1 and AMV.

Ac-Lys-Ala-Ser-Gln-Asn-Phe(NO2)-Pro-Val-Val-NH2 (peptide I) and Thr-Phe-Gln-Ala-Phe(NO2)-Pro-Leu-Arg-Glu-Ala (peptide II) undergo hydrolysis between the p-nitrophenylalanyl and prolyl residues catalyzed by the proteases of HIV-1 and AMV, respectively. The specific hydrolyses of peptides I and II are accompanied by a decrease in their uv absorption at 269 nm (delta epsilon = 1000) and an increase at 316 nm (delta epsilon = 600). The use of microspectrophotometric cells allows continuous uv measurements on a volume (60 to 120 microliters) comparable to that required for the HPLC point assay currently used. At the highest substrate concentration possible under the assay conditions, good first-order kinetics were observed with both proteases, and the values of Vmax/Km were obtained.

Avian Leukosis Virus↗
PubMed1989

Mutagenic specificity of a potent carcinogen, benzo[c]phenanthrene (4R,3S)-dihydrodiol (2S,1R)-epoxide, which reacts with adenine and guanine in DNA.

Mutations were induced in the supF gene of the pS189 shuttle vector by treatment with optically active benzo[c]phenanthrene (4R,3S)-dihydrodiol (2S,1R)-epoxide in vitro and replication in human cells. The induced mutation frequency was 60-fold greater than the spontaneous rate, and most of the mutations analyzed were transversions (86%), which principally consisted of similar numbers of A.T----T.A and G.C----T.A changes. The unusual susceptibility of A.T pairs to mutation by this chemical agent is consistent with its chemical reactivity toward adenine and argues that the mutations are targeted to the adducts formed. The central base in the sequences 5'-AGA-3', 5'-AAC-3', and 5'-GAG-3' was particularly susceptible to mutation. Twelve "hotspots" in the supF gene accounted for most mutations seen. Some of these hotspots differed from those found by others for racemic benzo[a]pyrene dihydrodiol epoxide and, even when a hotspot was common, the mutagenic changes were not always the same. Although adenine insertion opposite a noninstructional lesion could account for most of the data, no single mutagenic mechanism could encompass all of it. The cellular machinery that converts chemical damage to mutations must determine the mutational result to a large extent, but the findings herein show that the chemical agent itself plays a large role in determining both the location and the nature of the mutations that arise.

Adenine↗
PubMed1989

Molecular mechanics simulations on covalent complexes between polycyclic carcinogens and B-DNA.

We present molecular mechanics simulations on models of covalent complexes between the diol-epoxides of the carcinogens benzo[a]pyrene, benzo[e]pyrene and benzo[c]phenanthrene and a DNA pentamer d(GCGCG).d(CGCGC). In all the models, the carcinogen diol-epoxides lie in the minor groove with alkylation to the exocyclic amino group of the guanine. The theoretical calculations on the benzo[a]pyrene adducts to the pentamer are qualitatively consistent with the experimentally observed relative reactivities between various isomers. The adduct with the (+)trans isomer, which is the most carcinogenic of the benzo[a]pyrene stereoisomers, is calculated to be the energetically most favored. The relative energetic preferences in the adducts of benzo[e]pyrene diol-epoxides to the pentanucleotide parallel those of benzo[a]pyrene. However, there is no obvious explanation for the lack of biological activity in the diol-epoxides of the former carcinogen from the theoretical calculations. In the case of adducts with the diol-epoxides of benzo[c]phenanthrene, the energetically most favored structures are isomers with significant biological activity. The distortions in the double helix are more significant in the complexes with the diol-epoxides of this carcinogen compared to those in the complexes with the diol-epoxides of the other two carcinogens.

Benzo(a)pyrene↗
PubMed1988

Differential stereoselectivity on metabolism of triphenylene by cytochromes P-450 in liver microsomes from 3-methylcholanthrene- and phenobarbital-treated rats.

Metabolism of triphenylene by liver microsomes from control, phenobarbital(PB)-treated rats and 3-methylcholanthrene(MC)-treated rats as well as by a purified system reconstituted with cytochrome P-450c in the absence or presence of purified microsomal epoxide hydrolase was examined. Control microsomes metabolized triphenylene at a rate of 1.2 nmol/nmol of cytochrome P-450/min. Treatment of rats with PB or MC resulted in a 40% reduction and a 3-fold enhancement in the rate of metabolism, respectively. Metabolites consisted of the trans-1,2-dihydrodiol as well as 1-hydroxytriphenylene, and to a lesser extent 2-hydroxytriphenylene. The (-)-1R,2R-enantiomer of the dihydrodiol predominated (70 to 92%) under all incubation conditions. Incubation of racemic triphenylene 1,2-oxide with microsomal epoxide hydrolase produced dihydrodiol which was highly enriched (80%) in the (-)-1R,2R-enantiomer. Experiments with 18O-enriched water showed that attack of water was exclusively at the allylic 2-position of the arene oxide, indicating that the 1R,2S-enantiomer of the oxide was preferentially hydrated by epoxide hydrolase. Thiol trapping experiments indicated that liver microsomes from MC-treated rats produced almost exclusively (greater than 90%) the 1R,2S-enantiomer of triphenylene 1,2-oxide whereas liver microsomes from PB-treated rats formed racemic oxide. The optically active oxide has a half-life for racemization of only approximately 20 s under the incubation conditions. This study may represent the first attempt to address stereochemical consequences of a rapidly racemizing intermediary metabolite.

Animals↗
PubMed1987

Stereoselective formation of benzo(c)phenanthrene (+)-(3S,4R) and (+)-(5S,6R)-oxides by cytochrome P450c in a highly purified and reconstituted system.

The principal oxidative metabolites formed from benzo(c)phenanthrene (B(c)Ph) by the cytochromes P450 in liver microsomes from control and treated rats are the 3,4- and 5,6-arene oxides. A procedure is described which allows determination of the enantiomer composition and absolute configuration of these arene oxides based on HPLC separation of isomeric thiolate adducts formed with N-acetyl-L-cysteine in base. Incubation of [3H]-B(c)Ph with highly purified cytochrome P450c in a reconstituted monooxygenase system followed by trapping of the metabolically formed arene oxides as above indicated that the 3,4-oxide was predominantly the (+)-(3S,4R)-enantiomer (90%) and that the 5,6-oxide consisted mainly of the (+)-(5S,6R)-enantiomer (76%). The results are discussed in terms of their implications about the catalytic binding site of cytochrome P450c.

Animals↗
PubMed1986

Mechanism of inactivation of rat liver microsomal cytochrome P-450c by 2-bromo-4'-nitroacetophenone.

The mechanism by which 2-bromo-4'-nitroacetophenone (BrNAP) inactivates cytochrome P-450c, which involves alkylation primarily at Cys-292, is shown in the present study to involve an uncoupling of NADPH utilization and oxygen consumption from product formation. Alkylation of cytochrome P-450c with BrNAP markedly stimulated (approximately 30-fold) its rate of anaerobic reduction by NADPH-cytochrome P-450 reductase, as determined by stopped flow spectroscopy. This marked stimulation in reduction rate is highly unusual in that Cys-292 is apparently not part of the heme- or substrate-binding site, and its alkylation by BrNAP does not cause a low spin to high spin state transition in cytochrome P-450c. Under aerobic conditions the rapid oxidation of NADPH catalyzed by alkylated cytochrome P-450c was associated with rapid reduction of molecular oxygen to hydrogen peroxide via superoxide anion. The intermediacy of superoxide anion, formed by the one-electron reduction of molecular oxygen, established that alkylation of cytochrome P-450c with BrNAP uncouples the catalytic cycle prior to introduction of the second electron. The generation of superoxide anion by decomposition of the Fe2+ X O2 complex was consistent with the observations that, in contrast to native cytochrome P-450c, alkylated cytochrome P-450c failed to form a 430 nm absorbing chromophore during the metabolism of 7-ethoxycoumarin. Alkylation of cytochrome P-450c with BrNAP did not completely uncouple the catalytic cycle such that 5-20% of the catalytic activity remained for the alkylated cytochrome compared to the native protein depending on the substrate assayed. The uncoupling effect was, however, highly specific for cytochrome P-450c. Alkylation of nine other rat liver microsomal cytochrome P-450 isozymes with BrNAP caused little or no increase in hydrogen peroxide formation in the presence of NADPH-cytochrome P-450 reductase and NADPH.

Acetophenones↗
PubMed1986

Chemical modification and inactivation of rat liver microsomal cytochrome P-450c by 2-bromo-4'-nitroacetophenone.

The alkylating agent 2-bromo-4'-nitroacetophenone (BrNAP) binds covalently to each of 10 isozymes of purified rat liver microsomal cytochrome P-450 (P-450a-P-450j) but substantially inhibits the catalytic activity of only cytochrome P-450c. Regardless of pH, incubation time, presence of detergents, or concentration of BrNAP, treatment of cytochrome P-450c with BrNAP resulted in no more than 90% inhibition of catalytic activity. Alkylation with BrNAP did not cause the release of heme from the holoenzyme or alter the spectral properties of cytochrome P-450c, data that exclude the putative heme-binding cysteine, Cys-460, as the major site of alkylation. Two residues in cytochrome P-450c reacted rapidly with BrNAP, for which reason maximal loss of catalytic activity was invariably associated with the incorporation of approximately 1.5 mol of BrNAP/mol of cytochrome P-450c. Two major radio-labeled peptides were isolated from a tryptic digest of [14C]BrNAP-treated cytochrome P-450c by reverse-phase high performance liquid chromatography. The amino acid sequence of each peptide was determined by microsequence analysis, but the identification of the residues alkylated by BrNAP was complicated by the tendency of the adducts to decompose when subjected to automated Edman degradation. However, results of competitive binding experiments with the sulfhydryl reagent 4,4'-dithiodipyridine identified Cys-292 as the major site of alkylation and Cys-160 as the minor site of alkylation by BrNAP in cytochrome P-450c.

Acetophenones↗
PubMed1986

Disposition of the naturally occurring antimutagenic plant phenol, ellagic acid, and its synthetic derivatives, 3-O-decylellagic acid and 3,3'-di-O-methylellagic acid in mice.

The effect of ellagic acid and some of its more lipophilic derivatives on the mutagenicity of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenz[a]pyrene was examined in Salmonella typhimurium TA100. Ellagic acid, 3,3'-di-O-methylellagic acid, 4,4'-di-O-methylellagic acid and 3-O-decylellagic acid were found to have approximately equal antimutagenic activity. The tissue distribution and elimination of ellagic acid, 3,3'-di-O-methylellagic acid and 3-O-decylellagic acid were examined in CD-1 mice. Little or no ellagic acid (less than 1 nmol/g) was found in blood, lung or liver after the oral administration by gavage of 300 mumol of ellagic acid per kg body weight of after feeding 1% of ellagic acid in the diet for 1 week. Following the i.p. administration of 120 mumol/kg of ellagic acid, the blood and lung levels of ellagic acid were 15-20 nmol/g at 30 min after the dose, and the concentrations of ellagic acid decreased to 1-3 nmol/g at 6-8 h after the dose. A portion of the administered i.p. dose precipitated in the abdominal cavity. After i.v. administration, ellagic acid was eliminated very rapidly from blood, lung and liver, and approximately 70% of the administered dose was recovered in the urine and feces as free ellagic acid and its conjugates. At 2 h after an i.v. injection of 60 mumol/kg of ellagic acid, 46% of the dose was recovered in the urine as ellagic acid and its conjugates. Of this amount, about half was excreted as free ellagic acid and half was excreted as conjugates. An additional 25% of the dose was recovered in the feces (mostly as free ellagic acid) after 7 h. The disposition of 3,3'-di-O-methylellagic acid or 3-O-decylellagic acid after i.v. administration (32 mumol/kg) was examined and compared to the disposition of the same i.v. dose of ellagic acid. The concentrations of ellagic acid, 3,3'-di-O-methylellagic acid and 3-O-decylellagic acid decreased rapidly in the blood, liver and lung, but the concentrations of 3-O-decylellagic acid in the lung throughout the experimental period (2-360 min) was on average 20- to 40-fold higher than the corresponding average concentrations of ellagic acid or 3,3'-di-O-methylellagic acid.

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