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A J Ryan

Publications and source records attributed to A J Ryan.

189 records · Page 11Linked to original sources
PubMedDate not supplied

Stereochemistry of the major rodent liver microsomal metabolites of thecarcinogen dibenz[a,j]acridine.

The major metabolites of the carcinogen dibenz[a,j]acridine formed in rodent liver microsomal preparations were trans-3,4-dihydroxy-3,4-dihydrodibenz[a,j]acridine (DBAJAC-3,4-DHD) and dibenz[a,j]acridine 5,6-oxide (DBAJAC 5,6-oxide) [Gill et al. (1987) Carcinogenesis 8, 425-431]. The enantiomers of DBAJAC-3,4-DHD were prepared from the separable diastereoisomeric esters with (+)-endo-1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hept-5-ene-2-carboxyl ic acid (HCA). The absolute configuration of trans-3(R),4(R)-dihydroxy-1,2,3,4-tetrahydrodibenz[a,j]acridine was assigned by conversion to the bis[p-(dimethylamino)benzoate] and examination of the exciton coupling in its circular dichroic (CD) spectrum. The 3(R),4(R)-tetrahydrodiol was converted to DBAJAC-3(R),4(R)-DHD. The enantiomers of DBAJAC 5,6-oxide were partially resolved by chiral stationary-phase chromatography, and subsequent methoxide attack afforded two enantiomerically enriched isomeric ethers from each fraction. The structures of the two ethers from each enantiomer were determined, and from their 1H NMR spin-spin coupling between the H5 and H6 signals and the CD spectra of the ethers, the absolute configuration of the ethers, and hence the 5,6-oxides, was determined. The enantiomeric composition of the 3,4-dihydrodiol and 5,6-oxide formed as microsomal metabolites of rat liver preparations was 69% 3R,4R and 81% 5R,6S, respectively. When rats were pretreated with 3-methylcholanthrene (MC), these percentages were 70% and 5%, indicating a reversed stereochemical preference for oxide formation in the MC-induced preparation. Results are also presented for phenobarbitone-induced rat liver and mouse liver preparations.

Acridines↗
PubMedDate not supplied

The metabolism of styrene oxide in the isolated perfused rat liver. Identification and quantitation of major metabolites.

Isolated perfused rat livers rapidly metabolized 14C-styrene oxide. A large proportion of the administered radioactivity was excreted in the bile as a single compound that was identified as S-(1-phenyl-2-hydroxyethyl)glutathione by comparison with an authentic synthetic standard. The circulating perfusate was found to contain approximately equal amounts of styrene glycol, mandelic acid, and the glutathione derivative.

Animals↗
PubMedDate not supplied

Urinary metabolites of 3,5-di-(1-[13C]methyl-1-methylethyl)4-hydroxytoluene (BHT-13C) in man.

Butylated hydroxytoluene (BHT) containing the stable isotope 13C was synthesized from 2-[13C]methylpropan-2-ol. A minor constituent of urine following ingestion of BHT-13C by a human volunteer was identified as 3,5-di-(1-[13C]methyl-1-methylethyl)-4-hydroxybenzoic acid, The major metabolite detected was 13C-labeled 5-carboxy-7-(1-carboxy-1-methylethyl)-3,3-dimethyl-2-hydroxy-2,3-dihydrobenzofuran. Detailed spectral analysis provided the basis for structural assignment. No evidence was found for intermediate metabolites leading from BHT-13C to the above compounds. Analysis of one fraction indicated the presence of traces of S-(3,5-di-(1-[13C]methyl-1-methylethyl-4-hydroxy-benzyl)-N-acetylcysteine. Analysis of serum samples by gas chromatography detected only trace quantities of unchanged BHT. No evidence was found for the presence of other nonpolar or unconjugated metabolites.

Butylated Hydroxytoluene↗
PubMedDate not supplied

The metabolism and excretion of 14C-styrene oxide-glutathione adducts administered to the winter flounder, Pseudopleuronectes americanus, a marine teleost. Identification of the corresponding S-cysteine derivatives as major urinary metabolites.

The metabolism and excretion of intramuscularly administered 14C-glutathione conjugates of styrene oxide (Ia and IIa) were studied in the winter flounder at three dose levels. The various radiolabeled thioether metabolites excreted were separated by reverse-phase high pressure liquid chromatography, and identified and quantitated by cochromatography with synthetic standards. The urine was the major excretion route for radioactivity derived from the glutathione conjugates (up to 90%) at each dose level (1.0, 3.9, and 24.4 mg/fish) studied. The corresponding cysteine derivatives (Ic, IIc) were the major urinary metabolites although the N-acetylcysteine derivatives (Id, IId), or mercapturic acids, were also present in significant amounts at each dose and excretion interval examined. Unchanged glutathione conjugates of styrene oxide were the major radioactive constituents of 24-hr bile samples from the treated flounder, although significant amounts of the cysteinylglycine (Ib, IIb), cysteine, and N-acetylcysteine derivatives were also present in bile. Bile was a minor excretory route relative to urine. The oxidation of 14C-styrene to styrene 7,8-oxide by the cytochrome P-450-dependent monooxygenase system of hepatic microsomes of winter flounder was also demonstrated; likewise, styrene was converted to the diastereomeric glutathione conjugates of styrene 7,8-oxide by 9,000g supernatant fractions of flounder liver supplemented with glutathione. This study demonstrated that flounder liver can convert styrene to glutathione conjugates to styrene oxide and that mercapturic acid biosynthesis occurs after parenteral administration of a xenobiotic-glutathione adduct to this marine species, although the major urinary metabolites were the cysteine conjugates rather than the anticipated mercapturic acid derivatives.

Acetylcysteine↗