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N R Pimstone

Publications and source records attributed to N R Pimstone.

At least 37 records · Page 2Linked to original sources
PubMed1984

Dual mechanism of inhibition of rat liver uroporphyrinogen decarboxylase activity by ferrous iron: its potential role in the genesis of porphyria cutanea tarda.

Hepatic iron overload amplifies the uroporphyrinogen decarboxylase enzyme defect in human porphyria cutanea tarda. To understand its mechanism, we studied the effects of iron on the enzyme activity from rat liver cytosol. Enzyme activity was inhibited about 50% by 0.10 mM Fe2+ or by 0.16 mM Zn2+ directly regardless of whether the cations were added immediately, or were first preincubated for 2 h at 37 degrees C in the absence or presence of oxygen. Cysteine (6.7 mM) protected the enzyme from inhibition by Fe2+ under strictly anaerobic preincubation conditions; cysteine also protected enzyme inhibition by Zn2+ even in the presence of oxygen. Under aerobic conditions, cysteine enhanced the inhibition by Fe2+ to about 70%. This additional 20% inhibition was reversed by vitamin E, an antioxidant. The results suggest dual inhibitory effects of iron (a) by direct interaction of Fe2+, as well as Zn2+, with the essential sulfhydryl group(s) of the enzyme and (b), indirectly, due to generation of free radicals in the presence of oxygen and an electron donor such as cysteine. These radicals might interact directly with the enzyme and/or oxidize the porphyrinogen substrates to nonmetabolizable porphyrins, which accumulate in porphyric patients.

Aerobiosis↗
PubMed1983

Tumour localization of uroporphyrin isomers I and III and their correlation to albumin and serum protein binding.

We were the first to report the superiority of uroporphyrin I (UROP I) as a tumour localizer when compared to haematoporphyrin derivative (HPD). In this study, we compared both isomers of UROP, i.e. I and III, in a KHJJ mammary carcinoma mouse model. Six and 18 h after UROP administration, the tumour, skin and gut porphyrin (P) content was quantitated. Tumour UROP I levels were always at least 50% higher than UROP III in tumour, whereas both isomers were barely detectable in the skin and gastrointestinal tract. We then explored the possibility that tumour P uptake might relate in part to the affinity of circulating P to mouse serum proteins (MSP), in particular, the major binding protein constituent, albumin. Copro-P III, deutero-P 2,4 disulphonic acid (DP), proto-P IX (PP) and heptacarboxylic P I (Hepta I) which in our mouse tumour model do not localize in malignant tissue, were compared to UROP I and III. The P was mixed with 0.775 microM human serum albumin (HSA) at different molar ratios (HSA:P range 2-8) and the unbound P concentration quantitated using an Amicon CF-25 membrane cone with centrifugation. The percentage free P was significantly higher for UROP I (92-98%) than III (82-95%) and significantly more than that observed with non-tumour localizing P studied. Similar data were obtained with MSP. This is consistent with the notion that enhanced uptake and retention (particularly UROP I) by malignant neoplastic tissue might reflect a higher affinity for UROP by tumour constituents than by circulating proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Current status of medical treatment of gallstones.

Medical dissolution of gallstones is feasible and has worked in clinical practice. Cholelithiasis is both common and a cause of significant morbidity nationally. Thus, to readdress the question posed in the introduction, should there be a more aggressive detection of populations at risk to consider prophylactic or early treatment of gallstones, one has to consider the following. Is it cost effective to treat people with asymptomatic stones when one half of gallstones detected at autopsy have not caused trouble in life? Will the reduction of one health hazard create other hazards, such as colonic cancer? Is it improving the quality of the patient's life after successful treatment to have the person return every year for ultrasound or radiologic check-ups for recurrence of gallstones? We feel that despite the low morbidity and mortality of elective surgery, medical dissolution of gallstones is a viable alternative, but, as with most medical decisions, the pros and cons of any therapy for cholelithiasis will ultimately be a decision based on the physician, the patient, and the situation. On the basis of what has been discussed in this review, the approach to treatment should involve a rational understanding of all alternatives.

Bile Duct Diseases↗
PubMed1979

Familial symptomatic porphyria in South Africa.

Seven members from 3 generations of a family investigated for evidence of symptomatic porphyria (SP) were found to be affected in varying degrees by the disease. Four had cutaneous lesions, while all 7 had biochemical abnormalities diagnostic for SP in their excreta, plasma or hepatic tissue. The results were obtained using the highly sensitive technique of quantitative fluoroscanning after separation of the porphyrin methyl esters by thin-layer chromatography. This clear case of familial SP is rare in South Africa where the high incidence of the sporadic form of the disease is well documented. This study indicates that SP occurs in the following two forms: (i) the sporadic type, usually found as an uncommon associate of chronic liver disease; and (ii) the rare familial type, inherited as an autosomal dominant trait.

Adolescent↗
PubMed1979

Activation of uroporphyrinogen decarboxylase by ferrous iron in porphyria cutanea tarda.

Uroporphyrinogen decarboxylase was measured in the presence of ferrous iron, using mitochondria-free rat liver extracts as enzyme source. The activity of the enzyme was found to be increased at concentrations of ferrous iron from 0,01 mM, with maximal activity exhibited from 0,1 mM. Enzyme kinetics indicate that uroporphyrinogen decarboxylase reversibly binds ferrous iron, with a binding constant of approximately 5 x 10(4) mol-1. It is proposed that the effect of phlebotomy on patients with porphyria cutanea tarda is to mobilze storage iron in the liver to the active ferrous form, which activates hepatic uroporphyrinogen decarboxylase, the enzyme which is defective in this syndrome, with resultant clinical and biochemical remission.

Animals↗
PubMed1978

The nature of hepatic cytochrone P-450 induced in hexachlorobenzene-fed rats.

1. The effect of feeding with a diet containing 0.2% (w/w) hexachlorobenzene on hepatic and urinary porphyrins and hepatic cytochrome P-450 was studied at various time intervals in female Wistar rats. 2. Hexachlorobenzene administration for 45 days resulted in the development of porphyria in rats, which biochemically closely resembles symptomatic porphyria in humans, with elevation of urinary uroporphyrin excretion, hepatic uroporphyrin content, and hepatic cytochrome P-450 content, in addition to appearance of porphyrins of the isocoproporphyrin (P1) series in the faeces. 3. Spectral studies of the induced hepatic cytochrone P-450 at 45 days with carbon monoxide and ethyl isocyanide as ligands indicated the presence of a greater admixture of a haemoprotein distinct from cytochrome P-450. 4. Study in vitro of the kinetics of two reactions, namely aminopyrine N-demethylation and 3,4-benzpyrene hydroxylation, catalysed by the hepatic microsomal cytochrom P-450-dependent enzyme system, suggested that hexachlorobenzene induced a form of cytochrome P-450-dependent enzyme system, suggested that hexachlorobenzene induced a form of cytochrome P-450 with different catalytic properties from those of forms induced by either phenobarbital or 3-methylcholanthrene.

Animals↗
PubMed1976

Hepatic haem metabolism in porphyria cutanea tarda (PCT): enzymatic studies and their relation to liver ultrastructure.

Hepatic levels of cytochrome P-450 are elevated more than 4-fold in porphyria cutanea tarda (PCT) but not in other hepatic porphyrias or in non-porphyrics with alcoholic liver disease. In this study the ability of liver homogenates to metabolise aminopyrine and benzpyrene was correlated with hepatic cytochrome P-450 levels and with liver ultrastructure. The Km and Vmax for aminopyrine-N-demethylation and for benzpyrene hydroxylation exhibited a wide range of values with no significant differences between PCT patients and nonporphyric controls. Proliferation of the hepatic smooth endoplasmic reticulum in PCT was not significantly different from that observed in liver tissue obtained from patients with variegate porphyria or protoporphyria. Kushner reported data suggesting diminished uro'gen-I-decarboxylase activity as the autosomal dominantly inherited metabolic defect in PCT. Red cell uro'gen-I-decarboxylase activity was measured in 5 PCT males and 4 PCT females and activities were compared with 16 sex- and age-matched non-porphyric control patients. There was no significant difference in uro'gen-I-decarboxylase activity in the PCT and non-porphyric patients nor was there any significant difference relating to the sex of the patient. The role of iron in PCT was studied indirectly using the hexachlorobenzene porphyric rat as the rodent model.

Aminopyrine↗
PubMed1976

The hepatic lesion in protoporphyria (PP): preliminary studies of haem metabolism, liver structure and ultrastructure.

Five unrelated patients with protoporphyria (PP) had diagnostic liver biopsies performed to assess the degree of liver damage. The porphyrin content of the liver was quantitated and characterized and liver damage was assessed. Ultraviolet (UV) microscopy was performed in each case. Liver structure was assessed by light, polarization and electron microscopy. In 3 patients the liver was visualized directly before biopsy through a peritoneoscope. Liver damage ranged from minimal cell necrosis to portal fibrosis; the latter was observed in a 27-year-old sib of a patient (M.I.) who had died, aged 29, 3 years previously in liver failure from PP-related cirrhosis. Liver tissue from the latter patient which was obtained at the time of autopsy was re-examined by light and polarization microscopy. Hepatic pigment deposits, thought to be lipofuscin, showed birefringence on polarization microscopy in two cases, one of them being patient M.I. with PP-cirrhosis. Liver fluorescence on UV microscopy was centrizonal, punctate, faded rapidly and was easily distinguishable from that seen in porphyria cutanea tarda (PCT). The porphyrin content of the liver tissue in biopsied patients was between 5 mug and 80 mug, and in the autopsy case 1600 mug protoporphyrin/g wet weight liver, and on thin layer chromatography only dicarboxylic porphyrins were demonstrable. Hepatic cytochrome P-450 levels in protoporphyria were within normal range. Vmax and Km for aminopyrine-N-demethylation and benzpyrene hydroxylation did not differ significantly from our findings in PCT, variegate porphyria in remission and in non-porphyric controls. However, the activity of hepatic delta-aminolaevulinic acid (ALA) synthetase was significantly enhanced in 2 of the 3 patients in whom this measurement was performed.

Adult↗