Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 8 Porphyrins and the Porphyrias
life span. In addition, the decrease in heme synthesis
induces an increase in the survival time of the reticulocyte
by inhibiting the maturation of the developing erythrocytes,
which further aggravates the anemia. This biochemical
defect in heme synthesis is morphologically expressed
in the fluorocytes and in the evidence of erythrogenic
response in the blood and bone marrow, the degree of
which is directly related to the severity of the enzymatic
defect of the porphyria.
e . Detection of the Carrier State
Bovine CEP is inherited as an autosomal recessive trait.
Previously, carrier animals were detectable only by the
occurrence of the disease in their progeny. Levin (1968a)
developed an assay for UROgenIII-Cosyn and found that
its activity was considerably less in CEP cattle than in
normals ( Levin, 1968b ). Heterozygous cattle, which are
the clinically unaffected carriers of the porphyria gene,
had UROgenIII-Cosyn activities intermediate between
porphyrics and normals ( Romeo et al. , 1970 ). Similarly
low UROgenIII-Cosyn activity is found in human CEP,
but carriers are less readily detectable in humans than in
cattle ( Romeo and Levin, 1969 ). These findings are also
in keeping with the concept that the genetic defect in CEP
is a deficiency of UROgenIII-Cosyn. Romeo (1977) has
reviewed the genetic aspects of all forms of hereditary porphyrias
and determined that the evidence is conclusive for
a UROgenIII-Cosyn deficiency in CEP.
f . Metabolic Basis of Bovine Congenital Erythropoietic
Porphyria
The mechanisms for heme biosynthesis and the biochemical
nature of the porphyrins in the tissues and excreta provide
an explanation for the metabolic defect in CEP. Certain
features of the biosynthetic mechanism are particularly
important in an explanation of the clinical and metabolic
manifestations of CEP, which has its ultimate pathogenesis
in a hereditary deficiency of UROgenIII-Cosyn. These may
be summarized as follows:
1. There is a compartmentation of the enzymes of heme
biosynthesis between the mitochondria and the cytosol.
2. Mitochondrial systems are involved in the synthesis of
ALA, PROTO IX, and heme.
3. Cytosolic systems catalyze the formation of PBG,
UROgenIII or I, and COPROgenIII or I.
4. Mitochondria are present only in the immature
nucleated erythropoietic cells and in the reticulocytes.
Mitochondria are not present in the mature erythrocyte.
The most active heme and hemoglobin synthesis occurs
in the metarubricyte and secondly in the reticulocyte.
5. There is no heme or hemoglobin synthesis in the
mature erythrocyte.
The enzymatic deficiency in CEP is localized in the
erythropoietic tissue within the developing erythropoietic
cells, which are the mitochondria-containing cells.
Normally, the combined action of UROgenI-Syn and
UROgenIII-Cosyn catalyzes the formation of the normal
type III porphyrin isomer, UROgenIII leading to the
formation of heme. In the absence of UROgenIII-Cosyn,
the type I isomer, UROgenI, and then COPROgenI are
formed. Thus, the relative activities of these enzymes govern
the extent as to which of these pathways is traversed.
The type I isomers that are formed in the deficiency state
cannot be converted into PROTOgenI and thus into a
type I heme. This is because there is no coproporphyrinogen
I oxidase and the COPROgenIII-Ox is highly specific
only for the type III isomer. The type UROgenI and
COPROgenI isomers are oxidized to their corresponding
uroporphyrins and coproporphyrins. These oxidized free
porphyrins accumulate in the erythropoietic tissues, developing
erythrocytic cells, and in the mature erythrocytes
where they induce the hemolysis characteristic of CEP.
In addition, the porphyrins are released into the circulation
and are widely distributed throughout the body in all
body fluids and are readily excreted in the feces and urine.
They are deposited in all tissues, most notably in the teeth,
bones, and skin. When exposed to ultraviolet light, the porphyrins
in the skin are excited by absorption of the ultraviolet
light energy into an unstable higher-level energy state.
The excitation energy is then emitted when the excited
molecule returns to its ground state. The energy can be
emitted as fluorescence or transferred to molecular oxygen
to form singlet oxygen. Singlet oxygen is a powerful oxidant
for many forms of biologically important compounds
including the peroxidation of membrane lipids, membrane
and cellular proteins, cell enzymes, and cell organelles.
Peroxidation appears to be the primary event in the photosensitivity
and photodermatitis seen in the porphyrias
(Poh-Fitzpatrick, 1982 ).
Total deficiency of UROgenIII-Cosyn is obviously
incompatible with life so that surviving cases of CEP have
only a partial deficiency of UROgenIII-Cosyn. Also, there
is a wide variation in the severity of the disease commensurate
with the degree of the enzyme deficiency as well as
with the conditions of husbandry. The severity of the disease,
however, is constant in each bovine if it is kept under
standard controlled conditions. The metabolic basis for
bovine CEP is summarized in Figure 8-4 , in which the central
theme is the genetically controlled UROgenIII-Cosyn
deficiency with the resultant type I porphyrin accumulation
and a failure of heme synthesis.
2 . Bovine Erythropoietic Protoporphyria
This disorder of porphyrin metabolism occurs in humans
and in cattle. Erythropoietic protoporphyria (EPP) was
first reported by Magnus et al. (1961 ), and is now well