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Biomedical subjects

S Cottrell

Publications and source records attributed to S Cottrell.

At least 19 recordsLinked to original sources
PubMed2000

Methapyrilene hepatotoxicity is associated with increased hepatic glutathione, the formation of glucuronide conjugates, and enterohepatic recirculation.

The mechanisms by which acute administration of methapyrilene, an H(1)-receptor antihistamine causes periportal necrosis to rats are unknown. This study investigated the role of the hepato-biliary system in methapyrilene hepatotoxicity following daily administration of 150 mg/kg per day over 3 consecutive days. Biliary metabolites of methapyrilene were tentatively identified. In male Han Wistar rats administration of methapyrilene significantly increased hepatic reduced glutathione (GSH) to 140% of control levels 24 h following the last dose. There were no significant changes in the activities of glutathione-related enzymes, glutathione peroxidase (GPx) and reductase (GSH), glutathione S-transferase (GST), and gamma-glutamyl cysteine synthetase (gamma-GCS) over 3 days of methapyrilene administration. Methapyrilene treatment resulted in no significant increase in excretion of biliary oxidized glutathione (GSSG), a sensitive marker of oxidative stress in vivo, following the third dose. [3H]Methapyrilene-derived radioactivity was detected in bile, to a greater extent than in feces, indicating that methapyrilene and/or metabolites underwent enterohepatic recirculation. Cannulation and exteriorization of the bile duct (to interrupt enterohepatic recirculation) afforded some protection against the hepatotoxicity, assessed by clinical chemistry and histopathology. Liquid chromatography-mass spectrometry (LC-MS) analysis of bile indicated the presence of unmetabolized methapyrilene, methapyrilene O-glucuronide and desmethyl methapyrilene O-glucuronide. These data demonstrate that acute methapyrilene hepatotoxicity in vivo is not a consequence of GSH depletion, or oxidative stress, but that enterohepatic recirculation of biliary metabolites may be important. Progressive exposure to non-oxidizing, reactive metabolic intermediates may be responsible for hepatotoxicity.

Alanine Transaminase↗
PubMed1999

A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp.

Imprinting on human chromosome 15q11-q13 is controlled by a bipartite imprinting center (IC) that maps to the SNRPN locus. Deletions of the IC result in an imprinting defect and Prader-Willi syndrome or Angelman syndrome (AS). We have now identified a 5-kb IC deletion in an English AS patient (AS-LO); this represents the smallest microdeletion found in AS and narrows down the shortest region of deletion overlap to 880 bp.

Angelman Syndrome↗
PubMed1999

Visual evoked potential evidence of albino-like chiasmal misrouting in a patient with Angelman syndrome with no ocular features of albinism.

An 8-month-old boy with global developmental delay, including visual and hearing inattention, was examined in the ophthalmic clinic. Monocular flash visual evoked potentials demonstrated a crossed asymmetry in scalp distribution, a feature considered to be pathognomic of albinism. Remarkably a foveal reflex was noted in each eye and this patient did not have nystagmus, iris transillumination, nor conspicuously pale fundi. The optic discs appeared normal. He was noted to have very fair skin and hair, with a small head and flat occiput. Cytogenetic studies demonstrated a microdeletion of the maternal chromosome 15q11-q13, and he was diagnosed with Angelman syndrome.

Albinism↗
PubMed1999

A 28-kb deletion spanning D15S63 (PW71) in five families: a rare neutral variant?

Methylation analysis with probe PW71 (D15S63) is an established procedure to test patients suspected of having Prader-Willi syndrome or Angelman syndrome. Using this test, we have identified a 28-kb deletion spanning D15S63 in five independent families. Sequence analysis revealed identical breakpoints in all the families. The haplotype data are compatible with a common ancestral origin of the deletion in at least two families. The deletion was not found in 1, 000 unrelated controls. Although the deletion maps within the imprinting-center region, neither maternal nor paternal inheritance of the deletion appears to affect imprinting in proximal 15q. We conclude that the deletion is a rare neutral variant that can lead to false-positive results in the PW71-methylation test.

Adolescent↗
PubMed1998

The LEC rat possesses reduced hepatic selenium, contributing to the severity of spontaneous hepatitis and sensitivity to carcinogenesis.

The hepatic concentrations of copper, zinc, magnesium, calcium, and selenium were measured in LEC rats, which develop a spontaneous form of hepatitis at 3-4 months of age, and compared to trace metal concentrations in the LEA rat, its asymptomatic congenic strain. Consistent with results found by other groups, copper was found to accumulate within the liver of LEC rats to levels more than 50 times those measured in LEA rats. In addition, liver selenium concentration in LEC rats was found to be around 50% of that in LEA rats. The enzyme activity, and RNA for the selenium dependent enzyme, glutathione peroxidase, was also found to be reduced in LEC rat liver. These results indicate that hepatic selenium in the LEC rat is depleted and that, as a result of this, the capacity to protect cells from copper-induced free-radical damage is reduced.

Animals↗
PubMed1998

Effects of induction and inhibition of cytochromes P450 on the hepatotoxicity of methapyrilene.

The mechanisms by which the antihistamine drug methapyrilene causes acute periportal hepatotoxicity in rats are not yet elucidated. This study investigated the effects of modulators of cytochrome P450 (CYP) activity on the hepatotoxicity of methapyrilene and also the effect of methapyrilene on hepatic CYP. Pretreatment of male Han Wistar rats with beta-naphthoflavone, phenobarbitone, butylated hydroxytoluene, piperonyl butoxide, Aroclor 1254, or cobalt protoporphyrin IX, agents known to modify hepatic CYP, all afforded some degree of protection against a hepatotoxic dose of methapyrilene (150 mg/kg x 3 days p.o.), as assessed by clinical chemistry and histology. Total hepatic CYP depletion by cobalt protoporphyrin IX treatment indicated CYP-mediated bioactivation was a prerequisite for methapyrilene-induced hepatotoxicity. Protection against hepatic damage was strongly associated with beta-naphthoflavone induction of CYP1A and phenobarbitone-associated CYP2B induction. However, the role of CYP3A, which is constitutively expressed in the liver and induced by piperonyl butoxide, butylated hydroxytoluene, or Aroclor 1254, was unclear. Modulation of FAD monooxgenase activity by methimazole pretreatment was not associated with increased methapyrilene-induced hepatotoxicity. Methapyrilene treatment alone specifically decreased microsomal enzyme activity markers for CYP2C11, CYP3A, and CYP2A and pretreatment with all the hepatic enzyme-inducing agents specifically prevented the loss of CYP2C11. Together this suggested that CYP2C11 was responsible for the suicide substrate bioactivation of methapyrilene and the toxicologic outcome largely relied upon an abundance of detoxifying enzymes present in the liver.

Animals↗
PubMed1998

Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3.

A locus for Peutz-Jeghers syndrome (PJS) was recently mapped to chromosome 19p13.3. Each of 12 families studied was compatible with linkage to the marker D19S886. We have analysed 20 further families and found that the majority of these are consistent with a PJS gene on 19p13.3. Three families were, however, unlinked to 19p13.3 and none of the available PJS polyps from these families showed allele loss at D19S886. There were no obvious clinicopathological or ethnic differences between the 19p13.3 linked and unlinked families. There appears, therefore, to be a major PJS locus on chromosome 19p13.3 and the possibility exists of a minor locus (or loci) elsewhere.

Chromosomes, Human, Pair 19↗
PubMed1997

Hepatic and associated response of rats to pregnancy, lactation and simultaneous treatment with butylated hydroxytoluene.

This paper describes changes in the livers of rats fed diets containing butylated hydroxytoluene (BHT) over two generations in two separate studies. BHT did not produce tumours when tested for carcinogenicity in several studies by the conventional way. However, when BHT was given to rats in a two-generation carcinogenicity study, a high incidence of hepatic tumours was found in males but not in female rats of the F1 generation. A sequential study has been carried out to gain an insight into this unexpected finding, paying particular attention to the perinatal period. In the dose-ranging study designed to assess the tolerance of rats to BHT, groups of male and female rats (F0 generation) were fed diets calculated to deliver 0, 500, 750 and 1000 mg/kg body weight/day. Following a loading period of 5 wk the rats were mated. The BHT content of the diet was not adjusted during pregnancy and lactation. Owing to the normal increase in food consumption during lactation, intakes peaked at double the nominal value by 21 days after the birth of pups. At this time the pups (F1) were weaned onto control diet and maintained on it for 4 wk. At birth, the body weights of pups from the BHT-treated dams were comparable to those of the controls but at weaning the body weights of the pups from all three dose levels were less than those of the controls. At the termination of the experiment (4 wk after weaning), the pups from BHT-treated dams still weighed less than those from untreated controls. In the main experiment the F0 generation were fed 0, 25, 100 and 500 mg/kg body weight/day. Their offspring (F1 generation) were weaned on diets containing the same amount of BHT as the respective parents, apart from the group given the highest dose level (500 mg/kg body weight/day). This dose level was reduced to 250 mg/kg body weight/day at weaning in order to conform with previously published findings. The pups from the dams given the highest dose level were maintained on a dietary concentration of 250 mg/kg body weight/day for the entire study. A group of age-matched non-pregnant females was also studied and the results obtained compared with those from pregnant dams. Pups from all groups were examined at day 20 of gestation, at weaning (21 days after birth), and at 4 and 22 wk post-weaning. There were no effects on fertility and no increase in foetal abnormalities at any dose of BHT. Dams receiving BHT at a nominal dose of 500 mg/kg body weight/day showed liver enlargement accompained by induction of pentoxyresorufin O-depentylase and glutathione S-transferase, and proliferation of the endoplasmic reticulum. Pups from these dams were of the same weight at birth as controls but lost weight during the lactation period. This deficit was not recovered by the time the experiment was terminated. Hence, in two independent studies, the only significant finding in rats treated with BHT in utero and during lactation was that the weight gain of pups during lactation was less than expected when dams received at least 500 mg BHT/kg body weight/day. The body weight of pups did not return to normal following a return to a control diet for 4 wk. It is postulated that the retardation in weight gain of the pups could be due to inadequate milk production.

Animals↗
PubMed1997

Clinical and molecular features of the hereditary mixed polyposis syndrome.

BACKGROUND & AIMS: Various inherited syndromes predispose to the development of colonic juvenile polyps and colorectal cancer, with potential importance for sporadic tumorigenesis. This study describes features of a possibly new syndrome of atypical juvenile polyps and other colonic tumors and compares these features with those of known gastrointestinal tumor syndromes. METHODS: A large family, St. Mark's family 96, with a tendency to develop colonic polyps of mixed histological types is described. Genetic linkage to known polyposis syndromes has been tested. RESULTS: Adenomatous and hyperplastic polyps occur in affected members of the family, although the characteristic lesion is an atypical juvenile polyp. Some affected individuals have developed polyps of more than one type, and individual polyps may contain features of more than one histological type. Polyps can undergo malignant change. Typically, fewer than 15 polyps are found at colonoscopy and there is no extracolonic disease associated with the development of polyps. The family's polyps seem to be inherited in an autosomal-dominant fashion, but the disease is probably unlinked to candidate loci with importance in colorectal tumorigenesis, such as APC, hMSH2, and hMLH1. CONCLUSIONS: We term this family's disease hereditary mixed polyposis syndrome (HMPS). Although mutations in the putative HMPS gene may be responsible for syndromes such as juvenile and Peutz-Jeghers polyposes, HMPS may also be a distinct disease.

Adenomatous Polyposis Coli↗
PubMed1997

Counselling dilemmas associated with the molecular characterisation of two Angelman syndrome families.

We report the molecular characterisation of two families with Angelman syndrome referred for prenatal diagnosis, in which atypical molecular findings resulted in counselling dilemmas. The first is a familial case of Angelman syndrome in which the two affected children have mutations which affect the imprinting mechanism, as shown by the presence of paternal DNA methylation patterns at D15S63 and SNRPN and biparental inheritance of 15q11-q13 markers. DNA prepared from a 21 week fetal blood sample detected a fetus with normal maternal and paternal DNA methylation patterns at D15S63, but inheritance of the same maternal chromosome 15q11-q13 as the two affected sibs. This is probably a result of germline mosaicism in the mother. The second is a case of Angelman syndrome with an atypical deletion of 15q11-q13, which involves both unusual proximal and distal breakpoints. The deletion was characterised in order to assess the risk of Angelman syndrome in a second pregnancy in the mother of this child.

Angelman Syndrome↗
PubMed1996

Strain-specific enhancement or inhibition of coumarin hepatotoxicity in mice following pretreatment with two different liver enzyme-inducing agents.

Human exposure to coumarin continues despite controversy over its hepatotoxic potential. Greater understanding of human reactions to coumarin may be achieved by studying murine interstrain differences. The metabolic basis of coumarin hepatotoxicity and its modulation by liver enzyme inducers, beta-naphthoflavone (beta NF) and aroclor 1254 (ARO), were investigated in C3H/He and DBA/2 mice. Coumarin (200 mg/kg) was hepatotoxic to both strains, resulting in 2- to 15-fold plasma aminotransferase elevations, mild subcapsular linear hepatocyte necrosis after 24 hr, and, in some C3H/He mice, centrilobular necrosis. In this strain, beta NF pretreatment caused a 2- to 3-fold further increase in plasma aminotransferases and produced periportal necrosis. In contrast, ARO-pretreated C3H/He mice tended to exhibit lower plasma aminotransferases and occasional midzonal damage. Neither pretreatment significantly altered coumarin hepatotoxicity in DBA/2 mice. In C3H/He mice, hepatic microsomal metabolism of [3-14C]-coumarin via the 3-hydroxylation pathway doubled following both beta NF and ARO treatment. The contrasting nonresponsiveness of DBA/2 mice suggested that this pathway is linked to the Ah locus, which is defective in this strain. ARO treatment caused a maximal 5-fold increase in coumarin 7-hydroxylation in C3H/He mice, whereas DBA/2 mice were 30% less responsive. Potentiation of coumarin hepatotoxicity corresponded to an increase in the 3-:7-coumarin hydroxylation ratio. Pretreatment-dependent shifts in the location of hepatocyte damage may be related to changes in the translobular ratio of enzymes involved in activation and detoxication of coumarin. These data highlight how genetic background, individual variation, and xenobiotic-induced alterations in enzyme profiles, factors all relevant to human risk assessment, can influence the consequence of coumarin exposure.

Alanine Transaminase↗
PubMed1994

Loss of heterozygosity on chromosome 5 in sporadic ovarian carcinoma is a late event and is not associated with mutations in APC at 5q21-22.

Frequent loss of heterozygosity in ovarian carcinoma (OC) has been reported on several different chromosomes. We have studied 27 OCs and corresponding normal tissue for loss of heterozygosity (LOH) using 10 markers detecting polymorphisms on chromosome 5 (two on 5p and eight on 5q). Three tumours showed extra copies, rather than loss, of one homologue. Twelve of 24 remaining tumours showed LOH on 5q (50%), and 8 of 21 on 5p (38%). Of the 12 showing LOH on 5q, 7 showed reduction to homozygosity at all informative markers over the chromosome. The remaining 5 showed LOH over all of 5q. These data are consistent with the localisation of a tumour suppressor gene on 5q involved in OC. A good candidate is the APC gene, which is mutated in a number of adenocarcinoma derived from several tissues and is located at 5q21-22. The APC gene was studied in 40 ovarian tumours, including all the OCs showing LOH, by single-strand conformation polymorphism (SSCP). Analysis of all the exons containing published mutations (approximately 4.7 kb of the cDNA) did not reveal any band shifts that could be attributed to mutations. However, a new polymorphism was detected, as well as 7 known polymorphisms. Together, these data indicate that (1) LOH is common on chromosome 5 in OC, (2) APC is not mutated in OC, and (3) another gene (or genes) on chromosome 5q is responsible for the LOH seen.

Adenocarcinoma↗
PubMed1994

The dose-dependent effect of BHT (butylated hydroxytoluene) on vitamin K-dependent blood coagulation in rats.

Earlier studies have reported a reduction of vitamin K-dependent blood clotting factor activity and incidence of haemorrhagic death in rats fed butylated hydroxytoluene (BHT); however, the vitamin K status of the animals used in these studies was claimed to be inadequate. The aim of the study reported here was to determine the effect of BHT on vitamin K-dependent clotting factors in vitamin K-sufficient and vitamin K-supplemented rats. Rats given BHT (3000 mg/kg body weight) for up to 21 days, in a diet containing a minimum of 3 ppm vitamin K3 (six times the recommended requirement), showed decreased vitamin K-dependent blood clotting factor activities, demonstrated by increases in factor-specific clotting time assays. Clotting times were prolonged within 7 days, significantly increased within 14 days (P < 0.001) and maximally increased 5.5-fold at 21 days (P < 0.05). Supplementation with a further 250 ppm vitamin K3 reversed this effect. BHT did not increase prothrombin time (PT), the usual index of clotting. However, in a similar 14-day investigation, a small but significant increase in PT (up to 151%, P < 0.005) was seen within 7 days. Further vitamin K supplementation was incapable of reversing this effect completely. A similar trend was shown by activated partial thromboplastin time. The 1/51 dilution Thrombotest, a more sensitive indicator of vitamin K-dependent clotting factor activity in the rat, was significantly increased (more than four fold, P < 0.01) within 7 days. This increase was fully reversed by further vitamin K supplementation. Prolongation of Thrombotest time was significant at a BHT dose level of 600 mg/kg body weight per day and this could be reversed by further supplementation of only 3.0 ppm vitamin K. However, at dose levels of 125 mg BHT/kg body weight per day or less, no clotting defects were observed. These studies confirm that chronic administration of more than 600 mg BHT/kg/day to rats supplied with recommended amounts of vitamin K can depress clotting factors and precipitate haemorrhagic deaths. When further vitamin K is provided, these deaths could be prevented even though not all clotting abnormalities may be reversed. This study disapproves the proposal that BHT-related clotting factor defects are confined to rats of inadequate vitamin K status, but shows that such effects do not occur at dose levels lower than 600 mg/kg/day. The results further indicate that rats receiving a high dose of BHT have a higher vitamin K requirement than would otherwise be considered necessary. However, as BHT produces no clotting defects in these animals receiving an intake 1000 times the acceptable daily intake, such clotting effects are most unlikely to indicate a human safety problem for BHT.

Animals↗
PubMed1994

Phenotypic expression in familial adenomatous polyposis: partial prediction by mutation analysis.

The phenotypic expression in familial adenomatous polyposis (FAP) is variable. This study compares the phenotype of 27 patients with an identical 5 base pair (bp) deletion at codon 1309 with a group of 61 matched patients with FAP where knowledge of specific mutations is not available and with seven other different mutations in 24 subjects. Patients with the codon 1309 deletion have significantly more colorectal polyps at the time of colectomy than age and sex matched FAP controls (p = 0.0001). The median number of polyps in colectomy specimens of patients with the deletion at codon 1309 was 4000 (interquartile (IQ) range 3000-4875), compared with 600 (IQ range 488-1400) in the matched controls. Mutations at codon 1323, 1407, and 233 were also associated with large numbers of polyps. Desmoid disease and extracolonic cancers were more common with the mutation at codon 1309 (p = 0.003). In conclusion, there may be a correlation between a specific germline mutation and the number of large bowel polyps. There is residual heterogeneity in phenotypic expression, however, and this may result from the influence of other genes, specific environmental factors or chance.

Adenomatous Polyposis Coli↗
PubMed1993

A long-range restriction map of human chromosome 5q21-q23.

A long-range restriction map encompassing the APC (adenomatous polyposis coli) gene has been constructed. The map includes 35 DNA markers and consists of two segments of 10 and 2.5 Mb. Published genetic markers have been connected using additional, nonpolymorphic DNA probes. The map clarifies marker order and allows comparison of physical and genetic data.

Adenomatous Polyposis Coli↗
PubMed1993

Two cases of 5q deletions in patients with familial adenomatous polyposis: possible link with Caroli's disease.

Two cases are reported of patients with deletions of chromosome 5q. Both have familial adenomatous polyposis (FAP) and mild mental retardation. In both, macroscopic polyposis was confined to the proximal colon in adult life (in their thirties) although microscopic adenomatosis was shown in the more distal colon with occasional single polyps. Both subjects had dermoid cysts, and congenital hypertrophy of the retinal pigment epithelium (CHRPE) was seen in case 2. Case 1 has gastroduodenal polyps and desmoid tumours; case 2 has a marfanoid habitus with an abnormal pectus, wasted calf muscles and clawing of the toes, and Caroli's syndrome. His deletion is cytogenetically more extensive than that in case 1. The paucity of adenomas in the left side of the colon suggests that FAP cannot always confidently be excluded by sigmoidoscopy alone. The expression of the disease in the colon in these cases could be milder than in the more usual autosomal dominant cases where nonsense mutations resulting from single base changes of small deletions rather than deletion of the whole gene are the usual finding.

Adenomatous Polyposis Coli↗
PubMed1992

Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas.

Mutations in the APC gene give rise to familial adenomatous polyposis (FAP) and also occur in many, perhaps most, sporadic colon cancers. By screening with single-strand conformation polymorphism analysis we identified several mutations in a small region of the APC gene in both FAP and sporadic cancers. These mutations were either point mutations or small deletions or insertions causing frameshifts, and all generated stop codons. One 5 base-pair deletion was found in a sporadic colon tumour, a colorectal cancer cell line derived from a sporadic colon tumour, and in four unrelated FAP patients. This mutation produces distinctive heteroduplex bands, which can be detected with a simple non-radioactive assay. Our findings suggest that highly localised short sequences, essentially runs that code for adenine and thymine, may account for up to 20% of all observed APC mutations.

Adenomatous Polyposis Coli↗