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J K Chipman

Publications and source records attributed to J K Chipman.

At least 91 records · Page 5Linked to original sources
PubMed1988

Inter-individual variation in the mutagenic activation of 2-acetylaminofluorene by human liver in relation to animal metabolic models.

A relatively large, reproducible inter-individual variation was found in the ability of 17 human liver S9 samples to mediate the mutagenicity of 2-acetylaminofluorene (2AAF) in Salmonella typhimurium strain TA98. In an animal model, variation in metabolic activation of 2AAF did not appear to relate to the phenotype of debrisoquine 4-hydroxylase since hepatic S9 from poor and extensive metabolizer phenotypes (female DA and female Wistar rat, respectively) mediated the mutagenicity of this aromatic amide equally well. Approximately one-third of human liver samples exhibited an ability to detoxify 2AAF in a modified bacterial mutagenicity assay in a manner similar to that shown by guinea pig (but not rat or rabbit) S9. However, only in 2/14 human preparations was the detoxification inhibited by 8-hydroxyquinoline which has previously been recognized as an inhibitor of a detoxifying 'transoxygenation' in guinea pig liver. The results support a growing body of evidence for inter-individual variation in human carcinogen metabolism which may be important in determining susceptibility to chemical carcinogenesis.

2-Acetylaminofluorene↗
PubMed1987

Mechanisms of butylated hydroxytoluene-mediated modulation of 2-acetylaminofluorene mutagenicity in rat and human hepatocyte/Salmonella assays.

Salmonella typhimurium (TA98) mutagenesis assays were used to study the influence of the antioxidant butylated hydroxytoluene (BHT) on 2-acetylaminofluorene (2-AAF) mutagenesis, in search of the mechanism of the anticarcinogenic effects of BHT. Rats pre-treated with BHT in the diet (0.5% w/w for 10 days) provided hepatocytes and hepatocyte S9 which were more efficient in the activation of 2-AAF than were similar preparations from control rats. The increased release of mutagens from hepatocytes might explain the reported increase in the incidence of bladder tumours in BHT-treated rats. In contrast, the mutagenic activity of 2-AAF was inhibited by the in vitro addition of BHT into incubations where human or rat liver S9 and intact hepatocytes were used for metabolic activation. Both competitive and un-competitive inhibition by BHT of 7-ethoxycoumarin O-deethylation was observed in hepatocytes which suggested that the antimutagenic activity may be mediated by one or more mechanisms of cytochrome P-450 inhibition. BHT inhibition of the mutagenicity of N-OH 2-AAF and of rat urinary metabolites of 2-AAF indicated that effects other than those mediated by cytochrome P-450 also occur e.g. scavenging of reactive metabolites. It was concluded that BHT-modulation of 2-AAF metabolic activation and mutagenesis (which may relate to BHT-protection against hepatocarcinogenicity) involves multiple mechanisms.

2-Acetylaminofluorene↗
PubMed1987

Activation of 2-amino-3-methylimidazo (4,5-f) quinoline in rat and human hepatocyte/Salmonella mutagenicity assays: the contribution of hepatic conjugation.

The capacity of human liver S9 and hepatocytes to metabolically activate 2-amino-3-methylimidazo (4,5-f) quinoline (IQ) in Salmonella mutagenicity assays more closely resembles that of preparations from Aroclor-induced rat than control rat. The extent to which hepatocyte conjugating enzymes contribute to activation in these assays has been studied. Omission of sulphate or addition of a 'specific' sulphotransferase inhibitor (2,6-DCNP) did not significantly reduce mutagenicity, nor did PAPS enhance S9-mediated bacterial mutagenicity. Conversely, mutagenicity was significantly inhibited by PCP (an inhibitor of both sulphotransferase and acetyltransferase) and an acetylation-deficient Salmonella (TA98/1,8DNP6) was unresponsive to the mutagenicity of IQ. These data suggest that acetylation but not sulphation is important in IQ bacterial mutagenesis. The addition of acetyl CoA, PAPS-generating system or ATP paradoxically reduces the mutagenicity of IQ in S9/Salmonella TA98 assays. Therefore, activation by esterification in hepatocytes does not contribute to the mutagenicity of IQ in Salmonella typhimurium possibly due to restricted access of conjugates into the bacterial cell.

Animals↗
PubMed1986

The formation and metabolism of N-hydroxymethyl compounds--IX. N-(acetoxymethyl)-4-chlorobenzamide: an electrophile but not a mutagen in Salmonella typhimurium.

The electrophilic properties of 4-chloro-N-(hydroxymethyl)benzamide as a model compound of carbinolamides formed during the metabolic oxidation of N-methylamides were investigated. 4-Chloro-N-(hydroxymethyl)benzamide did not react with nucleophiles such as cyanide or glutathione under physiological conditions. In contrast, N-(acetoxymethyl)-4-chlorobenzamide yielded the cyanomethylamide with KCN and S-(4-chlorobenzamidomethyl)glutathione with glutathione. Under nonaqueous conditions, N-(acetoxymethyl)-4-chlorobenzamide reacted avidly with ethanethiol, with methanol and with diethylamine in the presence of base, whereas 4-chloro-N-(hydroxymethyl)benzamide did not afford products under these conditions. These results show clearly that N-(acetoxymethyl)-4-chlorobenzamide is the precursor of reactive electrophilic methyleneimines. 4-Chloro-N-(hydroxymethyl)benzamide was not biotransformed to such electrophilic species when incubated with mouse hepatic microsomes or a microsomal supernatant with acetyl-CoA or a PAPS generating system. Neither 4-chloro-N-(hydroxymethyl)benzamide nor its acetate ester were mutagenic in the short term bacterial assay using Salmonella typhimurium. Nevertheless, esters of carbinolamides, such as N-(acetoxymethyl)-4-chlorobenzamide, might possess toxic or carcinogenic properties.

Animals↗
PubMed1986

The mutagenic potency of chrysoidines and bismark brown dyes.

Chrysoidine dyes are used by fishermen to colour bait and recent epidemiological evidence has suggested that this may explain why they are at increased risk of urothelial cancer. In recent years Bismark brown dyes have been used as chrysoidine substitutes. Previous mutagenicity studies on these azo-dyes have examined only one variety of dye and used only one type of activating enzyme. In this study six samples of chrysoidine and three samples of Bismark brown dye have been obtained from chemical suppliers and from angling sources. They have been analysed by n.m.r. spectroscopy to determine whether they contain ring methyl groups. The mutagenic potency of each dye has been assessed by the Salmonella typhimurium/mammalian microsomal mutagenicity assay utilizing the TA100 and TA98 stains. Those dyes with methyl substitutions have been found to be more potent mutagens than their non-methylated counterparts using either human or rat metabolic preparations and irrespective of whether the enzymes have been induced with phenobarbitone.

Animals↗
PubMed1985

Metabolism and enterohepatic circulation of benzo(a)pyrene-4,5-epoxide in the rat.

After i.v. administration of 3H-benzo(a)pyrene-4,5-epoxide (32.5 mumol/kg) to rats, 76% of the 3H appeared in bile within 3 h. The glutathione conjugate of benzo(a)pyrene-4,5-epoxide was the major biliary metabolite (33% of dose), together with a glucuronic acid conjugate of benzo(a)pyrene-4,5-diol (18%) and an unidentified metabolite (10%). The glutathione and glucuronic acid conjugates both undergo extensive enterohepatic circulation. Thus, following the intraduodenal administration of the 3H-labelled conjugates, 26% of the radioactivity was excreted in the bile after 24 h in the case of the glutathione derivative, and 40% in the case of the glucuronide. The benzo(a)pyrene-4,5-diol glucuronide, on enterohepatic circulation, appears in the bile in the same form as the conjugate administered with no evidence of further metabolism of the polycyclic hydrocarbon moiety. The glutathione conjugate of benzo(a)pyrene-4,5-epoxide, on recirculation, is reexcreted in bile as one unidentified metabolite, which is susceptible to the action of arylsulphatase.

Animals↗
PubMed1983

Mutagenicity and in vivo disposition of biliary metabolites of benzo(a)pyrene.

Rabbits and rats administered [3H]benzo(a)pyrene (BP; 40 mumol/kg, i.v.) excreted, via the bile, metabolites which increased reverse gene mutation frequency in Salmonella typhimurium TA98 when incubated with beta-glucuronidase. Glucuronic acid conjugates of BP 4,5-diol, BP 1,6-, 3,6- and 6,12-quinones were detected in rat bile with low levels of 3- and 9-OH BP and BP 7,8- and 9,10-diols. In rabbits BP 9,10-diol was the major aglycone along with smaller amounts of BP 1,6- and 3,6-quinones, BP 4,5- and 7,8-diols and 3- and 9-OH BP. Qualitatively similar metabolic profiles were found when animals were given 3 mumol/kg [3H]BP. When 3H-labelled biliary metabolites, which contained the mutagenic component, were administered intraduodenally to rats, radioactivity reached the systemic circulation but DNA adducts were not detectable (less than 0.03 pmol/mg DNA) in tissues (intestinal wall, liver and lung) exposed to the reabsorbed metabolites.

Animals↗
PubMed1982

Bile as a source of potential reactive metabolites.

Many toxic substances are excreted via the bile as chemically inert metabolites. In some cases, however, highly toxic, mutagenic and carcinogenic products can be derived from bile, either directly or after further metabolism by intestinal microflora or intestinal cells. Potential reactive substances may thus reach biliary tract and intestinal cells via this route and may undergo subsequent enterohepatic circulation. The possible role of biliary reactants in carcinogenesis of the biliary tract and intestine is discussed.

Amides↗
PubMed1982

Metabolism and excretion of benzo[a]pyrene in the rabbit.

1. Following i.v. administration of [14C]benzo[a]pyrene (3 mumol/kg) to rabbits, 30% of the 14C dose appeared in bile and 12% in urine, within six hours. 2. Biliary and urinary metabolites were mainly conjugated; less than 12% of the 14C was extractable with ethyl acetate, but after treatment with beta-glucuronidase or aryl sulphatase 30-40% became extractable. 3. H.p.l.c. analysis of the extracts indicated that the major non-polar metabolite was benzo[a]pyrene, 9,10-diol (18% of 14C in bile and 24% of 14C in urine, mainly conjugated with glucuronic acid). Smaller amounts of the 4,5-diol, the 3,6-quinone, and the 9-hydroxy- and 3-hydroxybenzo[a]pyrene were also found in bile (total less than 10%), together with 9-hydroxybenzo[a]pyrene and two unknown metabolites (X and Y) in urine (total less than 4%). 4. The proximate carcinogen, the 7,8-diol, was not detected in any extract. 5. After intraduodenal administration of biliary metabolites of [14C]benzo[a]pyrene (approx. 0 X 3 mumol), 14C was excreted in the bile (21% dose) and urine (14%) within 23 h, indicating that metabolites can undergo enterohepatic circulation in the rabbit.

Animals↗
PubMed1981

Metabolism and route of excretion of the chloro-cyclodiene HCE in the pigeon.

Male feral pigeons were fitted with re-entrant bile duct cannulae, or were colostomized to facilitate the separate collection of urine and feces. After administration of 15 mg kg(-1) of [14C]-HCE by intraperitoneal injection, collections of bile and urine were made to determine the routes of excretion and the major metabolites. Within seven hrs the percentages of injected 14C excreted were 16.2 2.9% in the urine of colostomized birds and 12.8 1.1% in the bile of cannulated birds. Since the rate of elimination of 14 C in the feces of colostomized birds was very low (29% dose in 12 days) compared with 59% in urine, apparently some biliary metabolites were reabsorbed from the gut prior to elimination in urine. Nearly all excreted material was in conjugated form. Biliary conjugates were predominantly glucuronides (greater than 84% of total 14C) whereas 96% of the conjugated material in urine was sulfate. Initial metabolism was predominantly oxidative with the formation of a monohydroxy epoxide (HHC), which was subsequently converted into two secondary metabolites (endo-HHC and dihydroxy-HCE). In contrast to other species, no measurable quantity of trans-diol was formed. The same pattern of initial metabolism was found in hepatic microsomes. The metabolism and excretion of HCE is slower in the pigeon than in the male rat, thus providing further evidence for the limited capability of the species to perform certain detoxifying transformations.

Animals↗
PubMed1981

Biliary excretion, systemic availability and reactivity of metabolites following intraportal infusion of [3H]benzo[a]pyrene in the rat.

Following the intraportal infusion of [3H]benzo[a]pyrene (BP) at two dose levels (5 and 0.125 mumol/kg) in the rat, metabolites were excreted via the bile and were released into the hepatic venous blood. At each dose level, a significant portion (approx. 15-18%) of biliary metabolites was directly extractable with ethyl acetate and a total of approx. 24-32% became extractable after incubation of bile with beta-glucuronidase. More than 65% and 70% of the 3H in blood and liver, respectively, was directly extractable with ethyl acetate. The h.p.l.c. profile of extracted metabolites was found to differ at the two dose levels studied. The binding of reactive metabolites to hepatic protein and DNa was measured at four dose levels of [3H]BP. The possible availability of hepatic-derived metabolites to extra-hepatic sites is discussed.

Animals↗