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E A Martin

Publications and source records attributed to E A Martin.

At least 37 records · Page 2Linked to original sources
PubMed1998

Strategies to improve the nutritive value of rice bran in poultry diets. III. The addition of inorganic phosphorus and a phytase to duck diets.

1. In the first of 2 experiments ducklings grown from 2 to 19 d were given diets with 0, 200 or 400 g rice bran, with or without a phytase and with 1 or 3 g inorganic phosphorus (Pi) per kg for rice bran-based diets only. In the 2nd experiment rice bran concentrations were 0, 300 or 600 g rice bran per kg with or without a phytase and 1 g Pi/kg. Ducks were grown from 19 to 40 d of age. 2. In experiment 1, a response to phytase was observed for weight gain and food intake on most diets except those with 200 g rice bran (3 g Pi) and 4.00 g rice bran (1 g P)i/kg. Main effects showed that 400 g rice bran depressed growth rate and food conversion ratio (FCR); increasing Pi depressed food intake, while food phytase increased food intake and growth rate over 2 to 19 d. There were several interactions. Dry matter and P retention were reduced but N digestibility improved when rice bran was increased from 200 g to 400 g/kg at 2 to 10 d of age; apparent metabolisable energy (AME) and calcium retentions were improved, similar results being seen at 10 to 19 d of age. Calcium and P retentions increased with the addition of food phytase and, at 10 to 19 d of age, phytase increased dry matter digestibility. Increasing Pi improved calcium and P retention, but only at 2 to 10 d of age. 3. Tibia ash (g or g/kg) content of bone was lowest on the diet without rice bran and without phytase; Pi concentration had no effect but phytase increased tibia ash on diets with 0 and 200 g rice bran and 1 g Pi/kg. Retention of several minerals in tibia ash declined at the highest rice bran inclusion rate; Pi level and phytase both increased Mg retention. 4. In experiment 2, food intake and growth rate of ducks, but not FCR, declined as rice bran inclusion increased from 0 to 600 g/kg. Phytase improved growth rate but not food intake and FCR on all 3 diets. Dry matter digestibility declined with increasing rice bran inclusion, but AME increased; retention of P and Mg declined but those of Ca and Fe increased. Phytase improved dry matter digestibility and retention of N and P. AME also increased but this was only on diets with 0 and 600 g rice bran/kg. There were reductions of 8% and 10% in P excreted in experiments 1 and 2 respectively when food phytase was added. 5. Tibia ash declined with increasing dietary inclusion of rice bran. Zn and Mn in ash tended to decline and Mg to increase; Ca and P showed no change in concentration in tibia ash. Again, phytase increased tibia ash content in bone. 6. It was concluded that there were a number of unexpected benefits from adding a food phytase to these diets, which resulted in improved nutrient yield and bird performance, although several of the diets appeared to be adequate in available P.

6-Phytase↗
PubMed1998

Strategies to improve the nutritive value of rice bran in poultry diets. IV. Effects of addition of fish meal and a microbial phytase to duckling diets on bird performance and amino acid digestibility.

1. Ducklings were given diets with vegetable protein (VP) and 0 or 600 g rice bran/kg; fish meal (60 g/kg) and a phytase (+, -) were added to the diets (VP + AP). An additional 40 g soyabean meal/kg was added to the diet with rice bran (VP ++). Amino acid digestibility and mineral retention were measured in the lower ileum of ducklings killed at 23 d of age. Acid insoluble ash was used as an inert marker. Trypsin and amylase activities were also measured and weights of the pancreas and small intestine recorded at slaughter. 2. Addition of soyabean meal (VP ++) to the diet with rice bran improved growth rate and food intake compared to the diet without (VP) and gave the same food intake and growth rate as the comparable basal diet (VP) without rice bran. Fish meal improved growth rate on the diets without rice bran and improved food intake on this diet (VP + AP). Rice bran depressed growth rate and food conversion ratio (FCR); protein source affected growth rate, food intake and FCR; phytase increased food intake only. There were several interactions. 3. Determined total amino acid composition of the diets appeared to meet the essential amino acid requirements of ducklings. Rice bran depressed the ileal digestibility of virtually all amino acids and phytase had no direct effect, although there were interactions. Fish meal addition to diets with rice bran improved the apparent digestibility of several essential amino acids as well as that of dry matter and crude protein. 4. Ileal retention of some minerals and tibia ash content were reduced by rice bran. Fish meal and phytase inclusion increased P retention and ash in tibia. 5. Higher intestinal trypsin activity and increased pancreas size were seen in ducklings on diets with rice bran compared to those without. Intestinal amylase activity was reduced in ducklings given rice bran, probably because of its low starch content. 6. The stimulating effect of fish meal on duckling performance was probably caused in part by the improvement in the digestibility of some amino acids. The addition of small amounts of minerals in fish meal may have increased mineral retention. Phytase gave benefits anticipated from our previous work, but also improved lysine and threonine digestibility in diets containing vegetable protein only.

6-Phytase↗
PubMed1998

Strategies to improve the nutritive value of rice bran in poultry diets. I. The addition of food enzymes to target the non-starch polysaccharide fractions in diets of chickens and ducks gave no response.

1. Three experiments were undertaken to test the efficacy of 2 enzymes targeting mainly the non-starch polysaccharides (NSPs) in rice bran. 2. In experiment one, 400 g rice bran/kg depressed chick performance and there was a significant decline in growth rate and food intake with increasing inclusion of rice bran (0, 200, 400 g). Neither enzyme had any benefit. 3. In experiment two, rice bran (inclusion 200 and 400 g/kg), did not alter growth rate, food intake or food conversion ratio of duckling (3 to 17 d of age). Again enzyme addition gave no response. 4. In experiment three, 300 g rice bran/kg stimulated duck (19 to 35 d of age) growth while 600 g rice bran/kg depressed growth but not food intake. Enzymes gave no response. 5. Relative gut viscosity declined with increasing rice bran inclusion as did dry matter in ileal digesta. There were differences between ducklings and chickens. 6. It was concluded that NSPs were not a significant factor in altering the nutritive value of rice bran and the enzymes used were therefore unlikely to be of benefit.

Animals↗
PubMed1998

Strategies to improve the nutritive value of rice bran in poultry diets. II. Changes in oil digestibility, metabolisable energy and attempts to increase the digestibility of the oil fraction in the diets of chickens and ducklings.

1. In experiment 1, the effects of age on oil digestibility and apparent metabolisable energy (AME) were measured in chickens and ducklings between 3 and 28 d of age on a diet with 400 g rice bran/kg. In experiment 2, a biosurfactant and a food lipase were added to diets of chickens containing 200 and 400 g rice bran/kg. In experiment 3, chicken diets containing 0 or 400 g rice bran/kg were supplemented with a food lipase (2 concentrations) or a food enzyme or their combination. 2. In experiment 1, oil metabolisability and AME increased substantially as chickens aged. Oil metabolisability was much higher in ducklings, when comparisons were made with chickens of similar age. 3. In experiment 2, lipase or biosurfactant gave no improvement in bird performance. Growth rate and food conversion ratio were, respectively, 23% and 10% better on diets with 200 compared to 400 g rice bran/kg. 4. In experiment 3, there was a significant growth response to lipase plus the enzyme mixture on the diet with 200 g rice bran/kg. On the diet with 400 g rice bran/kg, growth improvement was seen with the enzyme mixture only. 5. In experiment 3, enzyme addition did not increase oil metabolisability or AME. At 4 to 8 d of age AME was higher on the diet without rice bran but oil metabolisability was the same as on the diet with rice bran. At 19 to 23 d of age AME was similar but oil metabolisability was higher on the diet with rice bran than without. Droppings' dry matter was higher on diets without than with rice bran (32.4 vs 27.1%). 6. The response to lipase and the combination of this and a food enzyme suggest that there may be benefit in examining this interaction further although they had no effect on oil metabolisability or on AME. It is concluded that a stable AME for rice bran cannot be provided for chickens until at least 21 d of age.

Aging↗
PubMed1998

Evaluation of tamoxifen and alpha-hydroxytamoxifen 32P-post-labelled DNA adducts by the development of a novel automated on-line solid-phase extraction HPLC method.

A novel HPLC system has been developed that has allowed the separation of tamoxifen DNA adducts formed in the livers of rats and mice treated with this drug. At least 13 different peaks have been separated from 32P-post-labelled DNA, with two major peaks jointly accounting for >60% of the total adducts formed by tamoxifen in the livers of treated rats and mice. This is a great improvement on the resolution obtained by thin layer chromatography, which separates the adducts into one main product consisting of a group of major adduct spots eluting together, plus several other minor spots. Identification of the nature of some of the peaks has been investigated. Comparisons of the products formed when alpha-acetoxytamoxifen is reacted with DNA in vitro with 32P-post-labelled liver DNA adducts from rats treated with tamoxifen or alpha-hydroxytamoxifen in vivo, appear to confirm that a major route of activation of tamoxifen in vivo is via alpha-hydroxylation. The resolving power of this HPLC system has further extended this result to show that six of the peaks, including the two major peaks, are formed by the reaction of an activated alpha-hydroxytamoxifen with DNA. Activation of 4-hydroxytamoxifen by the peroxidase/H2O2 system in vitro gives a more polar DNA adduct seen only at trace levels in liver DNA from tamoxifen-treated rats and mice.

Animals↗
PubMed1997

Comparisons of the binding of [14C]radiolabelled tamoxifen or toremifene to rat DNA using accelerator mass spectrometry.

Tamoxifen, widely used as adjuvant therapy in the treatment of breast cancer, is now undergoing trials as a cancer chemopreventative agent. Previous work has shown an association between 32P-postlabelled adducts in rat liver DNA and the development of liver tumours. With the use of accelerator mass spectrometry, [14C]tamoxifen was shown to bind to liver DNA of female rats in a dose-dependent manner and was linear over 0.1-1 mg/kg, compatible with the therapeutic dose used in women (20 mg/person per day). Radiolabel could also be detected in extrahepatic organs, including reproductive and GI-tract, where levels were about 18 and 46%, respectively those seen in liver. Following enzymatic hydrolysis of liver DNA, normal nucleotides by HPLC showed < 2% incorporation of the [14C]radioactivity while > 80% appeared as non-polar products. In contrast, when animals were given an equivalent dose of [14C]toremifene, binding to DNA was an order of magnitude lower than that seen with tamoxifen and no evidence of non-polar adducted nucleotides following HPLC. However, in vitro, using human, rat or mouse liver microsomal preparations, NADPH-dependent binding of both toremifene and tamoxifen to calf thymus DNA could be demonstrated, suggesting that under favourable circumstances toremifene is capable of undergoing conversion to reactive intermediates.

Animals↗
PubMed1997

32P-postlabelling approaches for the detection of 8-oxo-2'-deoxyguanosine-3'-monophosphate in DNA.

32P-Postlabelling methods have been investigated for the analysis of the oxidative DNA damage lesion 8-oxoguanine. The extent of digestion of commercially available calf thymus DNA and an 8-oxo-2'-deoxyguanosine-3'-monophosphate (8oxodGp) containing oligonucleotide to 2'-deoxynucleotide-3'-monophosphates, using calf spleen phosphodiesterase and micrococcal nuclease, was determined by HPLC. The extent of unmodified nucleotide release from DNA, and the extent of 8oxodGp released from the oligomer did not increase between 1 and 16 h of incubation at 37 degrees C. Normal nucleotide release from DNA was found to be quantitative under these conditions, and 8oxodGp release from the oligomer was in the range of 84-91%. RNA contamination in DNA prepared for 32P-postlabelling severely compromised 8oxodGp analysis. Guanosine-3'-monophosphate (Gp) was found to exhibit similar chromatographic and electrophoretic properties to 8oxodGp and as such compromised both 8oxodGp isolation in enrichment steps and subsequent resolution of the 32P-labelled bisnucleotides by TLC. The effect of ribonuclease A, T1 and T2 was investigated and a combination of A + T1 was found to reduce Gp contamination in DNA samples to levels which no longer interfered with 8oxodGp analysis. We have successfully applied an HPLC enrichment protocol to the analysis of 8oxodGp in calf thymus DNA. Since determination of damage levels in human samples is often restricted by the amount of DNA available for analysis, a novel capillary electrophoresis (CE) technique for the enrichment of 8oxodGp has been developed. The advantage of CE is that it can achieve resolution of 8oxodGp and unmodified deoxynucleotides from much smaller samples and minimises the amount of [gamma-32P]ATP necessary for the analysis.

Autoradiography↗
PubMed1997

Tamoxifen causes gene mutations in the livers of lambda/lacI transgenic rats.

Tamoxifen, a rat liver carcinogen, was administered to female lambda/lacI transgenic rats at a dose of 20 mg/kg body weight by gavage for 6 weeks, and the animals were sacrificed 2 weeks later. Tamoxifen induced liver DNA adducts and caused a significant increase in mutation frequency (MF) of approximately 3-fold at the lacI gene in liver DNA. Liver DNA from animals dosed with tamoxifen at 10 mg/kg also showed a similar increase in MF. The mutations were characterized by a raised proportion of: (a) G:C to T:A transversions; (b) insertions of base pairs; and (c) deletions of pairs of G:C base pairs. These observations indicate that tamoxifen induces a distinct spectrum of mutations compared with that found in controls. Toremifene, a noncarcinogenic analogue of tamoxifen with similar estrogenic/antiestrogenic properties examined at 20 mg/kg body weight using the same dosing regime as tamoxifen was not mutagenic. A single oral dose of the rat liver carcinogen aflatoxin B1 (0.5 mg/kg) also significantly raised the MF. In conclusion, although tamoxifen is not mutagenic in regulatory short-term tests, it is a gene mutagen in the rat liver.

Aflatoxins↗
PubMed1997

Peroxidase activation of 4-hydroxytamoxifen to free radicals detected by EPR spectroscopy.

4-Hydroxytamoxifen is a major metabolite of the antiestrogenic drug tamoxifen used in the treatment of women with breast cancer. 4-Hydroxytamoxifen is broken down by a horseradish peroxidase/H2O2 system very much more rapidly than tamoxifen and causes much greater DNA damage determined by 32P-postlabelling. EPR spin trapping of 4-hydroxytamoxifen reaction products in the presence of the free radical trap 5,5-dimethyl-1-pyrroline N-oxide, together with glutathione as a hydrogen donor, resulted in the generation of a species with the characteristics of the glutathione thiyl radical (aN approximately 15.3 G, aH approximately 16.2 G). Support for the creation of thiyl radicals comes from the close to stoichiometric time dependent formation of glutathione disulfide concomitant with the loss of glutathione. Similar results were obtained using 4-hydroxytoremifene but no radical formation or glutathione loss could be detected using 3-hydroxytamoxifen (droloxifene). On-line LC-ESI MS analysis of the incubation products from 4-hydroxytamoxifen has identified three products with a protonated molecular mass of 773, consistent with the formation of dimers of 4-hydroxytamoxifen. The role that radical mechanisms have in the carcinogenic effects of tamoxifen in the endometrium or other target organs of women taking this drug remains to be established.

DNA Adducts↗
PubMed1997

Investigation of the formation and accumulation of liver DNA adducts in mice chronically exposed to tamoxifen.

Tamoxifen was administered to three strains of female mice (B6C3F1, C57BL/6 and DBA/2) in short- and long-term studies to determine their ability to activate tamoxifen and cause hepatic DNA damage. 32P-Postlabelling of liver DNA from mice treated for 4 days showed a group of major adducts that increased in a dose-dependent manner and co-chromatographed with the major adducts detected in rat liver. On cessation of dosing, the majority of adducts were cleared within 3 days. Binding of [14C]tamoxifen to DNA nucleotides was demonstrated by the use of accelerator mass spectrometry. In long-term studies of 12 months to 2 years duration, dependent on strain, tamoxifen was administered continuously in the diet to give a daily dose of approximately 40 mg/kg. DNA adducts were detected after 3 months, although the number of adducts decreased with time and by 2 years were not detectable in the tamoxifen treated mice. None of the treated groups showed a significantly increased incidence of liver tumours, with or without phenobarbital promotion and there was no sustained liver cell proliferation. Tamoxifen was detected in the mouse livers, but at levels 50 times lower than those reported in a comparable rat study. These results suggest that, in contrast to the rat, tamoxifen is non-carcinogenic in mice because it does not cause sufficient cumulative DNA damage, or act as a promoter by causing cell proliferation.

Animals↗
PubMed1997

Biomonitoring of possible human exposure to environmental genotoxic chemicals: lessons from a study following the wreck of the oil tanker Braer.

In January 1993 the oil tanker Braer ran aground in the Shetland Islands, Scotland. Approximately 80,000 tons of crude oil were released. Exceptionally high winds caused extensive pollution and exposure of the local population to crude oil. We describe the study which was immediately set in place to examine the exposed population for evidence of genotoxic exposure. Blood samples were taken and primary DNA damage was measured in the mononuclear cell fraction by the butanol modification of the 32P-postlabelling method. Mutation was measured at the hprt locus in T lymphocytes. No evidence of genotoxicity was obtained for either end point, but nevertheless, we believe that useful lessons were learnt, which should be incorporated into the design of future studies: (1) A rapid response is essential, and even if sufficient funds are not immediately available, it is still worth attempting to obtain samples quickly and use cryopreservation, also to attempt to estimate exposure. (2) Adequate numbers of volunteers must be sought, together with enough controls, not just to allow meaningful analysis but to overcome loss of samples and failure of things to go according to plan. (3) Points concerning laboratory practice include: (i) samples should be coded, (ii) clearly defined and proven protocols should be used, (iii) irreplaceable samples should not be used for method development, (iv) should a problem become apparent during the study, work on such samples should cease immediately until the problem is solved, (v) all critical experimental components should be pretested against a laboratory standard. (4) The study design should include replicate experiments to monitor experimental variability and reproducibility, as well as internal standards and cryopreserved "in house" samples. Care must be taken that samples from any one exposure group are spread between a number of independent experiments and that each experiment includes samples from a number of exposure groups. (5) A computerised data base should be maintained with full details of experimental variables, donor attributes, and raw data so that any contribution of experimental artefacts to "outlier" results can be monitored. (6) Because of the nature of the statistical variation for many environmental genotoxicity end points, only a large-scale study is likely to be capable of yielding useful information.

Accidents, Occupational↗
PubMed1996

Tamoxifen associated uterine pathology in rodents: relevance to women.

Rats administered tamoxifen for 3 months and then returned to a basal diet developed an increase in uterine weight for up to 9 months after tamoxifen exposure. Stereological analysis of the tamoxifen exposed rat uteri showed that there was a significant increase in the amount of uterine myometrium, for a further 9 months, subsequent to the discontinuation of tamoxifen. A low incidence of myometrial proliferations (deciduomas) and uterine tumours was found at the conclusion of the study (20 months). In contrast, continuous administration of tamoxifen to mice for 24 months produced hyperplasia of the uterine endometrial epithelium and atrophy of the myometrium for the first 3 months, followed by atrophy of both the endometrium and myometrium for the remaining 21 months of the study. No uterine tumours were found in mice treated with tamoxifen for 2 years. The use of stereological analysis on interim sacrifice rodent uteri indicated that sustained uterine tissue compartment effects can occur, with either the continuous administration of tamoxifen, or after its discontinuation. Tamoxifen can have an agonist and antagonist like effect on oestrogen activity in different tissue compartments of the mouse uterus, over the same time period. The particular relevance of the finding of uterine proliferation and atrophy in the rodent studies with tamoxifen is discussed with regard to women taking this drug.

Animals↗
PubMed1996

Effect of tamoxifen feeding on metabolic activation of tamoxifen by the liver of the rhesus monkey: does liver accumulation of inhibitory metabolites protect from tamoxifen-dependent genotoxicity and cancer?

Tamoxifen induces hepatocellular carcinomas in rats and is converted by rat hepatic cytochrome P450 enzymes into reactive metabolites capable of forming adducts with nucleic acids, proteins and chromosomal aberrations. In rats tamoxifen has also been shown to induce liver cytochrome P450 enzymes, to stimulate its own metabolism leading to greater covalent binding and to induce a higher degree of unscheduled DNA synthesis. This suggests that, at least in the rat, a sensitive species, tamoxifen may contribute significantly to its genotoxic and carcinogenic potential, by assisting its own metabolic activation. We have now investigated the effect of feeding tamoxifen to male and female Rhesus monkeys. A marked induction of the hepatic cytochrome(s) P450 is found in the monkey but, in spite of this, the in vitro metabolism of 7-ethoxyresorufin by microsomes from treated animals is markedly inhibited and so is the dealkylation of two other 7-alkoxyresorufin substrates. Evidence is presented for the accumulation in the liver of monkeys treated with tamoxifen of a powerful inhibitor of drug metabolism, and the inhibitor is identified as a metabolite of tamoxifen, its N,N-didesmethyl derivative. The level of 32P-postlabelled DNA adducts was considerably higher in rats given tamoxifen than in similarly treated monkeys. Also, whereas rats responded to tamoxifen treatment with a marked increase in covalent binding to microsomal protein, in the monkeys, where accumulation of the inhibitory metabolite in the microsomal fraction was also seen, covalent binding was not greater with microsomes from treated animals than in the corresponding controls. N,N-Didesmethyl-tamoxifen, added in vitro to human and rat microsomes, reduced significantly the extent of covalent binding, suggesting that the accumulation of the metabolite observed in the liver of primates may discourage the cytochrome P450-dependent conversion of tamoxifen into reactive derivatives and in this way protect against the formation of adducts. This mechanism may also contribute to protecting the primate against tamoxifen- induced liver cancer.

Animals↗
PubMed1995

Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: promotion by phenobarbital.

Tamoxifen administered in the diet (420 ppm) to Wistar rats (TOX:P) for only 3 months caused cumulative hepatic DNA damage as assessed by 32P-postlabeling, consistent with the proposal that tamoxifen is a genotoxic carcinogen in this species. Promotion of tumor development with phenobarbital after discontinuation of dietary tamoxifen resulted in the formation of liver carcinomas after 9 months. At 12 and 20 months in this study, the majority of these rats had liver carcinomas. Rats treated with tamoxifen for 3 months but not promoted with phenobarbital also developed liver tumors over a longer period of time. These tumors were predominantly adenomas, with one carcinoma, and occurred at a lower incidence than the tumors produced by promotion with phenobarbital. Rats treated with phenobarbital alone did not develop tumors after 20 months. Tamoxifen-induced DNA adducts were relatively persistent, with only a 38% decrease 3 months after tamoxifen treatment had been discontinued. This demonstrates that, in a susceptible species (the rat), tamoxifen can cause initiation of liver cancer after only 3 months exposure. It is proposed that the persistence of such DNA adducts may account for the ability of phenobarbital to promote a high incidence of liver carcinoma, even after discontinuation of tamoxifen treatment. These data are relevant to the concern for women given prophylactic tamoxifen for long periods in that even if there is a relatively small amount of cumulative tamoxifen-induced liver DNA damage, liver tumors could be promoted by other agents, even after the cessation of tamoxifen treatment.

Animals↗
PubMed1995

Peroxidase activation of tamoxifen and toremifene resulting in DNA damage and covalently bound protein adducts.

When [14C]tamoxifen was incubated with horseradish peroxidase and H2O2, two major metabolites, separated and identified by HPLC, were N-desmethyltamoxifen and tamoxifen N-oxide. Toremifene incubated in a similar system yielded N-desmethyltoremifene and toremifene N-oxide. No 4-hydroxylated metabolites were detected with either drug. When calf thymus DNA was included in peroxidase incubation mixtures, DNA damage, as assessed by 32P-postlabelling, could also be detected. The extent of damage caused by tamoxifen and toremifene was similar. The major adducts formed following incubation of DNA with tamoxifen had similar Rf values to two of the 32P-postlabelled adducts seen following dosing of rats with tamoxifen. Peroxidase was able to activate both drugs to derivatives which covalently bound to bovine serum albumin. The pH optimum for covalent binding and N-demethylation was near to pH 6.0. Results from liquid chromatography-electrospray secondary ion mass spectrometry suggest that tamoxifen and toremifene are metabolized by peroxidase to putative reactive epoxide intermediates responsible for the genotoxic effects. It is proposed that peroxidase oxidizes tamoxifen to a carbon-centred free radical which reacts with oxygen to form peroxy radicals capable of inserting an oxygen atom into tamoxifen. Lactoperoxidase and prostaglandin synthase are also able to catalyse tamoxifen N-demethylation and binding to protein. These data show that peroxidase can activate both tamoxifen and toremifene to an intermediate(s) that can damage DNA and covalently react with protein. Since it is known that women treated with tamoxifen can develop endometrial tumours, it may be relevant to determine whether activation of tamoxifen by peroxidases may contribute to its carcinogenic action at extrahepatic sites.

Animals↗
PubMed1995

DNA damage as assessed by 32P-postlabelling in three rat strains exposed to dietary tamoxifen: the relationship between cell proliferation and liver tumour formation.

Tamoxifen was administered in the diet (420 p.p.m.) to female F344 (Fischer), Wistar (LAC-P) and LEW (Lewis) rats to determine for each strain the early morphological and biochemical changes associated with the subsequent development of liver cancer. Hepatic DNA damage, as determined by 32P-postlabelling, showed a cumulative increase with time from 500 adducts/10(8) nucleotides at 30 days to almost 3000 adducts/10(8) nucleotides after 180 days, with little difference between strains at this time point. A significant strain difference was found in the number of adducts present in the Fischer rats at 90 days, compared to the Wistar and Lewis strains. There was a marked strain differences in the time to development of liver tumours. After 6 months treatment, both Wistar and Lewis rats had tumours while none were seen in the Fischer animals. After 11 months, all of the Wistar and Lewis rats had developed liver carcinoma, while the Fischer rats developed liver carcinoma by 20 months. Depression in cell proliferation, relative to age-matched controls, was seen in the livers of Fischer rats after six months of exposure to tamoxifen, in contrast to an increase in the Wistar and Lewis rats. This observation is consistent with the promotion of foci to tumours and the subsequent progression of tumours to carcinomas in the latter two strains. These data may assist in establishing the possible risk factors, such as extent of DNA damage and increased liver cell proliferation, to women with long-term prophylactic exposure to tamoxifen.

Animals↗