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Biomedical subjects

C Rhodes

Publications and source records attributed to C Rhodes.

At least 55 records · Page 3Linked to original sources
PubMed1987

A balanced approach to the detection, characterisation and mechanism of the toxicity of industrial chemicals.

Several thousands of new chemical entities are synthesised each year in the laboratories of the world. Currently there are estimated to be some 100,000 substances used commercially of the 7 million chemicals recorded by chemical abstracts (Ca 1.5%). Public attention is mainly attracted to the potential life threatening and ill health effects of chemicals such as systemic poisoning, carcinogenicity, teratogenicity and mutagenicity, although there are relatively few proven human chemical carcinogens, teratogens or mutagens. Many substances have been examined in animal toxicity studies for their acute toxic effects, far fewer for chronic toxic effects. The public's perception is that chemicals are toxic. In our laboratory, minimal to no lethal toxic effects were recorded for more than 60% of substances examined at doses below 2000 mg/kg/bwt by either oral or dermal routes. A similar spectrum of chemicals did not elicit skin or ocular irritant or skin sensitisation response in 70-80% of studies. Perversely although toxicity studies reasonably predict the probable human response following exposure, they are a focus of a strong public lobby supported by many scientists to curtail studies in experimental animals. Consequently, much effort is devoted towards the development of "alternative" in vitro and ex-vivo procedures. Often these are empirically based without consideration of the underlying fundamental physiology, biochemistry or toxic mechanism of action. Consequently there can be an over-estimation or expectation of their ability to predict potential toxicity. Attention is seldom directed towards the design requirements of the validation studies needed to test, performance and reproducibility and the evaluation of the parameters of sensitivity and specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Cloning and characterization of the beta-amylase gene from Bacillus polymyxa.

The gene for beta-amylase was isolated from Bacillus polymyxa by molecular cloning in B. subtilis. B. subtilis cells containing this gene express and secrete an amylase which resembles the B. polymyxa beta-amylase and barley beta-amylase in terms of the products it generates during carbohydrate hydrolysis. Starch hydrolysis with this beta-amylase produces maltose, not glucose, whereas maltotriose and cycloheptaose are resistant to the action of this beta-amylase. The enzyme has a molecular weight of approximately 68,000. Restriction endonuclease mapping demonstrated that the DNA inserted in pBD64 and containing the gene is approximately 3 kilobases in length.

Amylases↗
PubMed1986

Comparative pharmacokinetics and subacute toxicity of di(2-ethylhexyl) phthalate (DEHP) in rats and marmosets: extrapolation of effects in rodents to man.

Certain phthalate esters and hypolipidemic agents are known to induce morphological and biochemical changes in the liver of rodents, which have been associated with an increased incidence of hepatocellular tumors in these species. There is evidence that hypolipidemic agents do not induce these effects in either subhuman primates or man. The oral and intraperitoneal administration of di(2-ethylhexyl) phthalate (DEHP) to the marmoset monkey at doses up to 5 mmole DEHP/kg body weight/day for 14 days did not induce morphological or biochemical changes in the liver or testis comparable with those obtained in rats given the same amount of DEHP. In the marmoset, the excretion profile of [14C]-DEHP following oral, IP, and IV administration and the lower tissue levels of radioactivity demonstrated a considerably reduced absorption in this species compared to the rat. The urinary metabolite pattern in the marmoset was in many respects qualitatively similar to but quantitatively different from that in the rat; the marmoset excreted principally conjugated metabolites derived from omega- 1 oxidation. The pharmacokinetic differences between these two species indicate that the tissues of the marmoset are exposed to a level of DEHP metabolites equivalent to the complete absorption of a dose of Ca. 0.1 to 0.25 mmole DEHP/kg body weight/day without significant toxicological effects. These exposure levels are at least 100-fold greater than the worst estimates of incidental human exposure (ca. 0.0015 mmole/kg/day). They are comparable with the human therapeutic dose of many hypolipidemic drugs (ca. 0.15 mmole/kg/day), a dose at which it is claimed that there is an absence of morphological or biochemical changes to human or subhuman primate liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Genotoxicity studies on di-(2-ethylhexyl) phthalate and adipate and toxicity studies on di-(2-ethylhexyl) phthalate in the rat and marmoset.

These studies have provided evidence that DEHP and DEHA do not bind covalently to DNA and do not therefore possess the characteristics of a genotoxic agent (Lutz, 1982). This suggests that the tumours induced in the rodent liver may result from some non-genotoxic mechanism and supports the view that the weakly positive dominant lethal test seen on administration of DEHP by the ip (but not the oral) route (Singh et al. 1974) is unlikely to have resulted from a direct effect on the genome of the sperm cells. Although the mechanism responsible for the induction of tumours by high doses of DEHP in rodents is not clear, it would appear both from these studies and from work on hypolipidaemic agents, that peroxisomal proliferation and the induction of enzymes associated with this organelle are in some way implicated (Cohen & Grasso, 1981). Other studies have shown that changes of this type are produced by doses of hypolipidaemic agents that induce liver cancer in rodents (Cohen & Grasso, 1981) and our investigations have indicated that they were also prominent at dose levels of DEHP similar to those that induced liver cancer in the NCI study (National Toxicology Program, 1982). No cancer induction would be expected to occur in the absence of these changes. In our dose-response study in rats it was shown that at the lowest dose (50 mg/kg body weight/day, approximately equivalent to a dietary level of 1000 ppm) several effects seen with higher doses were not apparent and others differed only slightly from normal control values. This is particularly relevant to assessments of the risk posed by DEHP and DEHA present as contaminants in foods, since human exposure via the food chain has been estimated by Shiota, Chou & Nishimura (1980) as 30 micrograms/kg body weight/day, several orders of magnitude less than the lowest exposure level used in these experiments. In addition, our studies indicate that none of the changes found in the rat were observed in the marmoset, suggesting that rodents and primates differ fundamentally in their hepatic and testicular response to DEHP. Previous studies by other authors (reviewed by Cohen & Grasso, 1981) indicated that morphological changes in the endoplasmic reticulum and the proliferation of peroxisomes are not features of the response of monkeys and man to high doses of hypolipidaemic agents.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipates↗
PubMed1984

The absence of testicular atrophy and in vivo and in vitro effects on hepatocyte morphology and peroxisomal enzyme activities in male rats following the administration of several alkanols.

Previous studies have shown that ethylhexanol (2-EH) and its oxidation products, but not n-hexanol, produce hepatomegaly, peroxisomal proliferation and hypotriglyceridaemia. In the present studies we have confirmed that at 1 mmol/kg doses, neither the linear nor branched chain alcohols induce testicular atrophy, hepatomegaly, peroxisome proliferation or hypolipidaemia. In vivo, neither the free alcohols nor their metabolic products seem to be responsible for the activity of the parent plasticiser. The released monoesters are probably the more potent metabolic products responsible for the hepatomegaly, peroxisomal proliferation and hypolipidaemia. This contention is supported by the in vitro hepatocyte data which demonstrate the induction of peroxisomal oxidative enzymes by MEHP whereas the alcohols were without effects.

Alcohols↗
PubMed1984

Genes for alkaline protease and neutral protease from Bacillus amyloliquefaciens contain a large open reading frame between the regions coding for signal sequence and mature protein.

The genes for alkaline protease (apr[BamP]) and neutral protease (npr[BamP]) from Bacillus amyloliquefaciens have been isolated and expressed in Bacillus subtilis. The DNA sequences of apr[BamP] and npr[BamP] revealed, in each case, the presence of a large open reading frame. The inferred amino acid sequence of either gene contained a signal sequence and an additional polypeptide sequence ('pro' sequence) preceding the mature protein. Based on DNA sequence, the start point of translation has been identified as amino acid residue - 107 for apr[BamP] and -221 for npr[BamP]. To demonstrate that the start point of translation of apr[BamP] in vivo is probably at codon -107, codon -103 (AAA) was changed to an ochre (TAA) by site-directed mutagenesis. Alkaline protease was produced from this ochre mutant derivative of apr[BamP] only when the host strain was Su+. The presence of a pro sequence may be common to all of the secreted proteases from bacilli.

Amino Acid Sequence↗
PubMed1983

The fate of fenclozic acid in the gut and its effect on some aspects of gut metabolism.

In the rat [14C]fenclozic acid is not metabolized in the gut and passes into the portal blood unchanged. After intraduodenal administration of [14C]fenclozic acid, a small proportion of the dose binds to high molecular weight substances in the gut wall. The incorporation of L-[U-14C]leucine and N-[3H]acetyl-D-glucosamine into acid-precipitable materials by isolated mucosal cells and homogenates of gut mucosal cells was inhibited by fenclozic acid in a dose-dependent manner. Other non-steroidal anti-inflammatory drugs (indomethacin, phenylbutazone, prednisolone, salicylic acid and paracetamol) were tested for their potency as inhibitors of glycoprotein production by whole cell preparations and by homogenized gut cell preparations. Marked differences were observed in the inhibitory potency of indomethacin, paracetamol and salicylic acid in the two experimental systems. Fenclozic acid had no major effect on the rate of total glycoprotein production by the isolated perfused rat liver or by the duodenal mucosa in situ. Fenclozic acid displaces albumin-bound [3H]tryptophan and increases the level of hepatic tryptophan pyrrolase approx. threefold. The inhibition of gut glycoprotein production by fenclozic acid was not prevented by free tryptophan.

Amino Acids↗
PubMed1981

The enhanced biliary secretion of a taurine conjugate in the rat after intraduodenal administration of high doses of fenclozic acid.

1. The metabolic fate of [14C]fenclozic acid (ICI 54450) in rat was determined after intraduodenal administration at different doses. 2. Increasing the dose from 2 to 100 mg/kg resulted in a five-fold increase in drug-related material secreted in bile. 3. At a dose of 2 mg/kg the taurine conjugate was a relatively minor metabolite, whereas at 100 mg/kg this conjugate was the major metabolite in bile and urine. 4. Enhanced biliary secretion of the taurine conjugate in rats receiving multiple doses of fenclozic acid results in exposure of the intestinal cells to much greater concn. of drug-related metabolites.

Animals↗
PubMed1978

Serum carbenoxolone in patients with gastric and duodenal ulcer: Absorption, efficacy and side-effects.

The absorption of carbenoxolone sodium has been studied in 15 patients with gastric ulcer and eight patients with duodenal ulcer treated for four weeks. Blood levels of carbenoxolone showed a log distribution, varied markedly between patients, and were significantly higher after Biogastrone tablets (300 mg/day) than after Duogastrone capsules (200 mg/day). Serum carbenoxolone levels were similar in patients taking Biogastrone tablets before or after meals, and in patients taking Biogastrone tablets or Duogastrone capsules with or without antacids following chronic administration. Serum carbenoxolone levels were similar in patients whose gastric ulcers had or had not healed after four weeks' treatment. Serum carbenoxolone was significantly higher in patients who developed oedema, and was significantly correlated with age and with fall in plasma potassium. Carbenoxolone may exert its metabolic effects systemically, but its ulcer-healing effects topically; additional studies are needed to test this hypothesis.

Adult↗