Medical genetics / edited by Victor A. McKusick and Robert Claiborne.

Date:
[1973]
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Medical genetics / edited by Victor A. McKusick and Robert Claiborne. Source: Wellcome Collection.

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    THE PORPHYRIC DISEASES OF MAN Congenital Acute Intermittent Porphyria HEPATIC PORPHYRIAS Congenital Cutaneous Hepatic Porphyria Acquired Cutaneous Hepatic Porphyria Copro 1 PBC Deaminase (deficiency) left) is indicated by the thickhess of the color lines and the arrows. cutaneous hepatic porphyrias may reflect enzymatic abnormali- The large amounts of porphyrins excreted by patients with the ties at these levels of the pathway, but this is still speculative. clear. A high incidence of the disease, without familial pattern, has been ob¬ served among the Bantus of South Africa, a tribe that consumes large quantities of an iron-rich adulterated alcoholic beverage. An especially de¬ finitive relationship between exoge¬ nous chemicals and acquired hepatic porphyria was seen with the chemical agent hexachlorbenzene, a wheat fun¬ gicide whose ingestion proved to be responsible for an epidemic of ac¬ quired cutaneous porphyria in Tur¬ key. It was subsequently shown that hexachlorbenzene could induce hepatic porphyria in experimental animals. The Turkish experience was the first clear demonstration that a chemi¬ cal could induce hepatic porphyria in a human population free of genetic susceptibility. Since these observations with hexachlorbenzene were made, ab¬ normalities in hepatic porphyrin meta¬ bolism have been described in patients under treatment with various hor¬ mones such aTi stilbestrol and oral con¬ traceptive steroids, and various drugs such as griseofulvin, the sulfonamides, and tolbutamide. Apparently, many of the drugs that can exacerbate the he¬ reditary hepatic porphyric disease may also initiate porphyrinuria in seemingly normal persons—with what clinical sequelae, if any, not known. Very importantly, however, these drugs have made it possible to estab¬ lish experimental models of hepatic porphyria in animals of various types and in tissue cultures of liver cells. In the laboratory, a large number of structurally diverse chemicals have been found to induce hepatic porphy¬ rin synthesis. The chemicals appear to act in a common manner in the bio- synthetic pathway: via induction of the mitochondrial enzyme ala syn¬ thetase, which controls the rate limit¬ ing step in hepatic porphyria syn¬ thesis. A problem in studies of experi¬ mental hepatic porphyria is that of reconciling the chemical heterogeneity of the provocative agents with the ap¬ parent uniformity of their efl^ect on Glycine Succinyl CoA NADPH NADP ALA Synthetase ALA Flavoprotein Reduced Flavoprotein Porphyrins Fe^^-Protein Fe^^^-Protein- The drug-metabolizing enzyme sequence localized in liver cell microsomes is related to the heme pathiuay through cytochrome P-450, the heme protein that serves as the terminal oxidase in -?> Heme Cytochrome P-450 Reduced Cytochrome P-450 Hydroxylated Substrate Substraté the sequence. The -mbstrates oxidized may be either endogenous or exogenous in origin and are generally (though not always) biologically inactivated by such oxidative transformation. 117