S ummary . Experimental hepatic siderosis in the rat due to dietary iron overload produced increased urinary excretion of uro‐ and coproporphyrin which was further aggravated by concurrent drinking of alcohol. On the basis of these findings it is considered very likely that the invariable presence of hepatic siderosis in symptomatic porphyria is more than incidental and that the presence of excessive iron in the liver cells is an important factor determining the development of symptomatic porphryia. Liver ALA synthetase activity was increased in the alcohol‐consuming animals but iron overload alone had no effect on the activity of this enzyme. The mechanism whereby siderosis influences hepatic porphyrin metabolism is unknown. No effect on hepatic mitochondrial coproporphyrinogen oxidase was found. It is suggested that in the siderotic animals and in patients with symptomatic porphyria there is interference with a normal disposal route for excessive haem precursors.
Abstract. Several recent reports have shown that antibodies reactive with acetaldehyde (AcH)‐modified epitopes are present in alcoholics. However, similar antibodies have also been found in patients with nonalcoholic liver disease and control subjects. In each of these studies total immunoglobulin binding to the AcH‐modified proteins was measured, with no attempt being made to identify the classes of immunoglobulin involved. In the present study we employed an enzyme‐linked immunosorbent assay (ELISA) to assess the classes of immunoglobulin involved in this response, using plasma samples from 97 alcoholics with varying degrees of liver disease, 35 patients with non‐alcoholic liver disease and 33 control subjects. All three groups exhibited a large IgM response and a negligible IgG response. However, the alcoholics exhibited a significantly higher IgA response than either of the other groups. This suggests that the measurement of the IgA response to AcH‐modified epitopes may be a specific marker of ethanol abuse.
Abstract— Abnormalities involving haem biosynthesis have been postulated as underlying mechanisms in the aetiology of the neural manifestations of acute porphyria and of lead poisoning. This paper reports a study of the enzymes of the haem biosynthetic pathway and their control in mammalian brain. The activity of rat brain 6‐aminolaevulinate synthetase (ALA synthetase), 6‐aminolaevulinate dehydratase (ALA dehydratase), uroporphyrinogen I synthetase, uroporphyrinogen decarboxylase and ferrochelatase were found to be between 12.5 and 0.002% of the corresponding values for liver. This accords with the lower concentrations of total haem and cytochrome P 450 found in brain and with the slower rate of incorporation of [4‐ 14 C]ALA into brain haem in vivo . The subcellular distribution of radioactivity following intraventricular injection of [4‐ 14 C]ALA confirmed that the bulk of brain haemoproteins are intramitochondrial in contrast to liver where the major portion is microsomal. Brain haem biosynthesis was apparently unaffected by factors known to influence this pathway in liver, including starvation and treatment with allylisopropylacetamide or phenobarbitone. These findings suggest that brain haem requirements are considerably less than those of liver and are not subject to significant fluctuations under normal circumstances. Apparent non‐inducibility of ALA synthetase suggests that deficient haem and consequently haemoprotein production could result where other enzymes in the pathway become rate‐limiting due to genetic defects or inhibition by exogenous agents such as lead.
Abstract: γ‐Aminobutyric acid (GABA) concentration was determined in cerebrospinal fluid (CSF) of acute and chronic schizophrenic patients, in persons with psycho‐organic or personality disorders, and in nonpsychiatric controls. The mean CSF GABA level in the chronic schizophrenic patients was found to be significantly higher than in any of the other groups. No other statistically significant differences were found. Statistical analysis revealed that the elevated CSF GABA concentration in the chronic schizophrenic patients was unlikely to be caused by medication. These results are interpreted as evidence for possible primary or secondary GABAergic overactivity in the brain in chronic schizophrenia.
S ummary . Rats previously rendered siderotic by intraperitoneal administration of iron‐dextran became porphyric much more rapidly than non‐siderotic animals when fed hexachlorobenzene. Fluorescence microscopy showed that initially porphyrin storage was focal and confined to the centrilobular zone but later became diffuse throughout the lobule. Analysis of liver extracts by thin layer chromatography revealed only 8‐ and 7‐carboxyl porphyrins which also predominated in the urine. The patterns resembled those seen in patients with symptomatic porphyria. These data are interpreted as further evidence that siderosis is an important factor in the derangement of hepatic haem biosynthesis which leads to the development of symptomatic porphyria.
At least 4 possible mechanisms may be postulated to explain the neural manifestations of acute porphyria in the hereditary hepatic porphyrias. These are (i) excessive amounts of porphyrins or porphyrin precursors produced in the liver during acute attacks are transported to the central and peripheral nervous system, where they exert neurotoxic effects; (ii) unidentified metabolites of the aforementioned compounds may be responsible; (iii) in patients with these diseases there may be a metabolic defect in neural haem biosynthesis which is aggravated by precipitating factors, thereby leading to acute neural manifestations; and (iv) the hepatic and nervous system lesions may be metabolically quite unrelated. Each of these possibilities is considered, and evidence is adduced that a genetic defect in haem biosynthesis in the nervous system is the most plausible hypothesis.
Four patients suffering from variegate prophyria were investigated during acute attacks. Porphyrin and prophyrin precursor concentrations were determined in the urine, serum, cereborspinal fluid (CSF) and stools. Levels of delta-aminolaevulinic acid (ALA) and porphobillinogen were found to be very much lower in CSF than in serum sampled concurrently, and were well below levels at which these substances have been shown to exert effects on neural tissue in vitro. These findings cast doubt on the possibility that ALA or porphobilinogen is responsible for the production of the neural manifestations of acute porphyria.
'/%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h10080v5040H0z'/%3e%3cpath stroke='%23fff' stroke-width='.6' d='m0 0 6 3m0-3L0 3' clip-path='url(%23b)' transform='scale(840)'/%3e%3cpath stroke='%23e4002b' stroke-width='.4' d='m0 0 6 3m0-3L0 3' clip-path='url(%23c)' transform='scale(840)'/%3e%3cpath stroke='%23fff' stroke-width='840' d='M2520 0v2520M0 1260h5040'/%3e%3cpath stroke='%23e4002b' stroke-width='504' d='M2520 0v2520M0 1260h5040'/%3e%3cg fill='%23fff'%3e%3cuse xlink:href='%23d' x='2520' y='3780'/%3e%3cuse xlink:href='%23a' x='7560' y='4200'/%3e%3cuse xlink:href='%23a' x='6300' y='2205'/%3e%3cuse xlink:href='%23a' x='7560' y='840'/%3e%3cuse xlink:href='%23a' x='8680' y='1869'/%3e%3cuse xlink:href='%23e' x='8064' y='2730'/%3e%3c/g%3e%3c/svg%3e)
'%3e%3cpath fill='%23001489' d='M0 0v6h9V0z'/%3e%3cpath fill='%23e03c31' d='M0 0v3h9V0z'/%3e%3cg stroke='%23fff' stroke-width='2'%3e%3cpath id='d' d='m0 0 4.5 3L0 6m4.5-3H9'/%3e%3cuse xlink:href='%23b' stroke='%23ffb81c' clip-path='url(%23c)'/%3e%3c/g%3e%3cuse xlink:href='%23d' fill='none' stroke='%23007749' stroke-width='1.2'/%3e%3c/g%3e%3c/svg%3e)
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)