Alpha1 Antitrypsin
is an essential protease
inhibitor in blood plasma. It binds to a wide
range of proteases, such as elastase, trypsin,
chemotrypsin, thrombin, and bacterial proteases.
Its most important physiological effect is
the inhibition of leukocyte elastase, a protease
that breaks down the elastin of the pulmonary
alveolar walls. Deficiency of !1-antitrypsin
leads to increasing destruction of the pulmonary
alveoli, obstructive emphysema of the
lungs, and in newborns, a form of hepatitis.
Sunday, April 12, 2009
Alpha1 Antitrypsin
!1-Antitrypsin (1) in humans is a glycoprotein
composed of 394 amino acids and 12% carbohydrate.
It is coded for by a 10.2 kb gene with five
exons on chromosome 14
composed of 394 amino acids and 12% carbohydrate.
It is coded for by a 10.2 kb gene with five
exons on chromosome 14
Antitrypsin deficiency
The uninhibited action of leukocyte elastase on
the elastin of the pulmonary alveoli leads to
chronic obstructive pulmonary emphysema (1).
(Radiograph from N. Konietzko, Essen.) The
most frequent deficiency allele is Pi(Z). The
plasma concentration of !1-AT with genotype
PiZZ (homozygote) is usually about 12–15% of
normal (with the normal allele M). MZ heterozygotes
have 64%, and MS heterozygotes 86%
of MM homozygote activity. !1-Antitrypsin
deficiency in the lung can be corrected by intravenous
administration of !1-antitrypsin.
the elastin of the pulmonary alveoli leads to
chronic obstructive pulmonary emphysema (1).
(Radiograph from N. Konietzko, Essen.) The
most frequent deficiency allele is Pi(Z). The
plasma concentration of !1-AT with genotype
PiZZ (homozygote) is usually about 12–15% of
normal (with the normal allele M). MZ heterozygotes
have 64%, and MS heterozygotes 86%
of MM homozygote activity. !1-Antitrypsin
deficiency in the lung can be corrected by intravenous
administration of !1-antitrypsin.
!1-Antitrypsin: protein, gene, and important mutations
The !1-antitrypsin protein has three oligosaccharide
side chains at positions 46, 83, and
247. The protein is highly polymorphic because
of differences in the amino acid sequence and in
carbohydrate side chains. The reactive site is located
at position 358/359 (methionine/serine).
Clinically, the most important mutations affect
codons 213 (PiZ), 256 (PiP), 264 (PiS), 342 (PiZ),
and 357 (Pi[Pittsburgh]). The gene contains variant
restriction enzyme sites, which can be used
for reliable diagnosis. Today the diagnosis is
often made using the PCR reaction.
side chains at positions 46, 83, and
247. The protein is highly polymorphic because
of differences in the amino acid sequence and in
carbohydrate side chains. The reactive site is located
at position 358/359 (methionine/serine).
Clinically, the most important mutations affect
codons 213 (PiZ), 256 (PiP), 264 (PiS), 342 (PiZ),
and 357 (Pi[Pittsburgh]). The gene contains variant
restriction enzyme sites, which can be used
for reliable diagnosis. Today the diagnosis is
often made using the PCR reaction.
Synthesis of !1-antitrypsin
The !1-AT gene is expressed in liver cells (hepatocytes).
The gene product is channeled
through the Golgi apparatus and released from
the cell (secreted). The Z mutation leads to
aggregation of the enzyme in the liver cells,
with too little of it being secreted. The S mutation
leads to premature degradation. About
2–4% of the population in Central and Northern
Europe are MZ heterozygotes.
The gene product is channeled
through the Golgi apparatus and released from
the cell (secreted). The Z mutation leads to
aggregation of the enzyme in the liver cells,
with too little of it being secreted. The S mutation
leads to premature degradation. About
2–4% of the population in Central and Northern
Europe are MZ heterozygotes.
Reactive center of protease inhibitors
!1-Antitrypsin is one member of a family of
protease inhibitors that show marked homology,
especially at their reactive centers. Oxidizing
substances have an inhibitory effect and
inactivate the molecule. Smokers have a much
more rapid course of !1-AT deficiency disease
protease inhibitors that show marked homology,
especially at their reactive centers. Oxidizing
substances have an inhibitory effect and
inactivate the molecule. Smokers have a much
more rapid course of !1-AT deficiency disease
Blood Coagulation Factor VIII (Hemophilia A)
Hemophilia was the first major disease recognized
to be genetically determined. The Talmud
refers to its increased occurrence in males in
certain families, corresponding with X-chromosomal
inheritance. Hemophilia A results from
the deficiency of blood coagulation factor VIII;
hemophilia B results from a deficiency of factor
IX. Factor VIII functions as a cofactor in the activation
of factor X to factor Xa during the intermediate
phase of the coagulation cascade.
to be genetically determined. The Talmud
refers to its increased occurrence in males in
certain families, corresponding with X-chromosomal
inheritance. Hemophilia A results from
the deficiency of blood coagulation factor VIII;
hemophilia B results from a deficiency of factor
IX. Factor VIII functions as a cofactor in the activation
of factor X to factor Xa during the intermediate
phase of the coagulation cascade.
X-chromosomal inheritance of hemophilia A
A classic example of the X-chromosomal inheritance
of hemophilia A was seen in some royal
families in Europe in the nineteenth century
and the first half of the twentieth century.
of hemophilia A was seen in some royal
families in Europe in the nineteenth century
and the first half of the twentieth century.
Blood coagulation factor VIII
When activated by thrombin, factor VIII protein
consists of five subunits (A1, A2, A3, C1, C2) held
together by calcium ions (1). The inactive factor
VIII protein (2) contains three domains (A, B, C).
Domain A occurs in three homologous copies
(A1, A2, A3), domain C in two (C1, C2), and
domain B in one copy. In humans, the gene for
factor VIII (3) maps to the distal long arm of the
X chromosome in region 2, band 8 (Xq28). It
consists of 26 exons and spans 186000 base
pairs (186 kb), corresponding to about 0.1% of
the whole X chromosome. Noteworthy in this
gene are the large exon 14 (3106 base pairs),
which codes for the B domain, and a large intron
of 32000 base pairs between exons 22 and 23.
Most point mutations occur in DNA sequences
involving TCGA, the recognition sequence for
the restriction enzyme TaqI. It contains the
dinucleotide CG, which is easily mutated. Since
the cytosine of this dinucleotide is frequently
methylated and deamination of methyl cytosine
leads to C-to-T transition, mutations in
CG dinucleotide regions are frequent. Mutation
of TCGA to TTGA creates a stop codon (TGA), resulting
in a truncated factor VIII protein. Even a
stop codon at position 2307 leads to severe
hemophilia, although only the last 26 amino
acids are missing (Gitschier et al., 1985).
Polymorphic restriction sites (RFLPs, restriction
fragment length polymorphisms) can be utilized
for molecular genetic diagnosis of
hemophilia A (4). When present, a variant recognition
sequence (B*) for the restriction
enzyme BcII in the region of exons 17 and 18
produces a fragment of 879 base pairs and a
fragment of 286 base pairs; when it is absent, a
single fragment of 1165 base pairs results. This
can be used in RFLP diagnosis (5): The index
patient (II-1) with hemophilia A carries the 879
bp fragment. This fragment indicates the mutation.
His sister (II-2) has an affected son (III-2)
who also carries the 879 bp fragment, inherited
from his mother. A brother (III-1) carries the
1165-bp fragment and thus is not at risk for the
disease, because this is not linked to the mutation.
In addition to point mutations, factor VIII gene
rearrangements involving the long intron 22 are
frequent.
consists of five subunits (A1, A2, A3, C1, C2) held
together by calcium ions (1). The inactive factor
VIII protein (2) contains three domains (A, B, C).
Domain A occurs in three homologous copies
(A1, A2, A3), domain C in two (C1, C2), and
domain B in one copy. In humans, the gene for
factor VIII (3) maps to the distal long arm of the
X chromosome in region 2, band 8 (Xq28). It
consists of 26 exons and spans 186000 base
pairs (186 kb), corresponding to about 0.1% of
the whole X chromosome. Noteworthy in this
gene are the large exon 14 (3106 base pairs),
which codes for the B domain, and a large intron
of 32000 base pairs between exons 22 and 23.
Most point mutations occur in DNA sequences
involving TCGA, the recognition sequence for
the restriction enzyme TaqI. It contains the
dinucleotide CG, which is easily mutated. Since
the cytosine of this dinucleotide is frequently
methylated and deamination of methyl cytosine
leads to C-to-T transition, mutations in
CG dinucleotide regions are frequent. Mutation
of TCGA to TTGA creates a stop codon (TGA), resulting
in a truncated factor VIII protein. Even a
stop codon at position 2307 leads to severe
hemophilia, although only the last 26 amino
acids are missing (Gitschier et al., 1985).
Polymorphic restriction sites (RFLPs, restriction
fragment length polymorphisms) can be utilized
for molecular genetic diagnosis of
hemophilia A (4). When present, a variant recognition
sequence (B*) for the restriction
enzyme BcII in the region of exons 17 and 18
produces a fragment of 879 base pairs and a
fragment of 286 base pairs; when it is absent, a
single fragment of 1165 base pairs results. This
can be used in RFLP diagnosis (5): The index
patient (II-1) with hemophilia A carries the 879
bp fragment. This fragment indicates the mutation.
His sister (II-2) has an affected son (III-2)
who also carries the 879 bp fragment, inherited
from his mother. A brother (III-1) carries the
1165-bp fragment and thus is not at risk for the
disease, because this is not linked to the mutation.
In addition to point mutations, factor VIII gene
rearrangements involving the long intron 22 are
frequent.
Severity and factor VIII activity
Hemophilia occurs with a frequency of about 1
in 10000 male newborns. Severity and
frequency of bleeding are dependent on the
degree of residual factor VIII activity.
in 10000 male newborns. Severity and
frequency of bleeding are dependent on the
degree of residual factor VIII activity.
VonWillebrand Factors
VonWillebrand factor (vWF) is a complex multimeric
protein found in plasma, platelets, and
subendothelial connective tissue. It has two
basic biological functions: it binds to specific
receptors on the surface of platelets and subendothelial
connective tissue, and it forms bridges
between platelets and damaged regions of a
vessel. Furthermore, it binds to clotting factor
VIII and stabilizes it. Deficiency of vWF leads to
decreased or absent platelet adhesion and to
secondary deficiency of factor VIII (von Willebrand
disease or von Willebrand–Jürgens syndrome).
Hereditary deficiency of vWF is the
most common bleeding disorder in man, with a
frequency of about 1:250 for all forms, including
the mild ones, and about 1:8000 for severe
forms.
protein found in plasma, platelets, and
subendothelial connective tissue. It has two
basic biological functions: it binds to specific
receptors on the surface of platelets and subendothelial
connective tissue, and it forms bridges
between platelets and damaged regions of a
vessel. Furthermore, it binds to clotting factor
VIII and stabilizes it. Deficiency of vWF leads to
decreased or absent platelet adhesion and to
secondary deficiency of factor VIII (von Willebrand
disease or von Willebrand–Jürgens syndrome).
Hereditary deficiency of vWF is the
most common bleeding disorder in man, with a
frequency of about 1:250 for all forms, including
the mild ones, and about 1:8000 for severe
forms.
VonWillebrand cDNA and prepropeptide
Von Willebrand factor is formed in endothelial
cells, in megakaryocytes, and possibly in some
other tissues and is coded for by a large (178 kb)
gene with 52 exons of various sizes on chromosome
12 (12p12-pter). Several polymorphic restriction
sites (red arrows) exist. The cDNA of
vWF is about 8.7 kb long. The corresponding
mRNA codes for a primary peptide (preprovWF)
of 2813 amino acids, including a signal
peptide of 22 amino acids, a segment of 741
amino acids (vW antigen II), and a subunit of
four different domains (A–D), which together
make up more than 90% of the sequence. The
three A domains (A1–A3) in the middle contain
binding sites for collagen, heparin, and thrombocytes.
Three small B domains are on the carboxy
side of the D4 domain, before the two C
domains. vWF contains 8.3% cysteine (234 of
2813 amino acids), concentrated at the amino
and carboxy ends, whereas the three A domains
are cysteine-poor. After posttranslational modification,
the mature plasma vWF contains 12
oligosaccharide side chains (19% of the total
weight is carbohydrate).
cells, in megakaryocytes, and possibly in some
other tissues and is coded for by a large (178 kb)
gene with 52 exons of various sizes on chromosome
12 (12p12-pter). Several polymorphic restriction
sites (red arrows) exist. The cDNA of
vWF is about 8.7 kb long. The corresponding
mRNA codes for a primary peptide (preprovWF)
of 2813 amino acids, including a signal
peptide of 22 amino acids, a segment of 741
amino acids (vW antigen II), and a subunit of
four different domains (A–D), which together
make up more than 90% of the sequence. The
three A domains (A1–A3) in the middle contain
binding sites for collagen, heparin, and thrombocytes.
Three small B domains are on the carboxy
side of the D4 domain, before the two C
domains. vWF contains 8.3% cysteine (234 of
2813 amino acids), concentrated at the amino
and carboxy ends, whereas the three A domains
are cysteine-poor. After posttranslational modification,
the mature plasma vWF contains 12
oligosaccharide side chains (19% of the total
weight is carbohydrate).
Biosynthesis of the von Willebrand factors (vWF)
vWF is first formed as a prepropeptide. After the
signal peptide is removed, two pro-vWF units
attach to each other at their carboxy ends by
means of numerous disulfide bridges to form a
dimer. The dimers represent the repetitive
units, or protomers, of mature vWF. The provWF
dimers are transported to the Golgi apparatus,
where the pro-vWF (vW antigen II or
vWagII) is removed. Mature vWF and vWagII
are stored inWeibel–Palade bodies in epithelial
cells. The mature subunits and vWagII contain
binding sites for factor VIII, heparin, collagen,
ristocetin + platelets, and thrombin-activated
platelets.
signal peptide is removed, two pro-vWF units
attach to each other at their carboxy ends by
means of numerous disulfide bridges to form a
dimer. The dimers represent the repetitive
units, or protomers, of mature vWF. The provWF
dimers are transported to the Golgi apparatus,
where the pro-vWF (vW antigen II or
vWagII) is removed. Mature vWF and vWagII
are stored inWeibel–Palade bodies in epithelial
cells. The mature subunits and vWagII contain
binding sites for factor VIII, heparin, collagen,
ristocetin + platelets, and thrombin-activated
platelets.
Classification of vonWillebrand diseases
Von Willebrand disease is a heterogeneous
group of disorders divided into several subtypes.
In types I and III, the defect is quantitative;
in type II, qualitative. Dominant and recessive
phenotypes with vWF deficiency often cannot
be readily distinguished because heterozygosity
may not be manifest and can only be determined
by laboratory tests. Type I with subtypes
A and B is the most frequent group (70% of
all patients). vWF deficiency may simulate
platelet dysfunction or hemophilia.
group of disorders divided into several subtypes.
In types I and III, the defect is quantitative;
in type II, qualitative. Dominant and recessive
phenotypes with vWF deficiency often cannot
be readily distinguished because heterozygosity
may not be manifest and can only be determined
by laboratory tests. Type I with subtypes
A and B is the most frequent group (70% of
all patients). vWF deficiency may simulate
platelet dysfunction or hemophilia.
Cytochrome P450 Genes
Complex chemical substances, such as drugs or
plant toxins, are degraded by an oxidation system
(monooxygenases) in the endoplasmic reticulum
of liver cells. These enzymes (collectively
referred to as cytochrome P450) absorb
light maximally at 450 nm after binding to CO.
Cytochrome P450 is the last enzyme in the essential
electron-transporting chain in microsomes
of the liver and mitochondria of the
adrenal cortex. A large system of evolutionarily
related genes code for the different P450 proteins
in mammals.
plant toxins, are degraded by an oxidation system
(monooxygenases) in the endoplasmic reticulum
of liver cells. These enzymes (collectively
referred to as cytochrome P450) absorb
light maximally at 450 nm after binding to CO.
Cytochrome P450 is the last enzyme in the essential
electron-transporting chain in microsomes
of the liver and mitochondria of the
adrenal cortex. A large system of evolutionarily
related genes code for the different P450 proteins
in mammals.
Cytochrome P450 system
The cytochrome P450 system(1) consists of oxidizing
enzymes (mixed monooxygenases).
They represent the first phase of detoxification:
a substrate (RH) is oxidized to ROH utilizing atmospheric
oxygen (O2), with water (H2O) being
formed as a byproduct. A reductase delivers hydrogen
ions (H+) either from NADPH or NADH. A
characteristic feature of P450 enzymes (2) is
that a single chemical substrate can frequently
be degraded by several P450 enzymes and that
a single P450 protein can oxidize a number of
structurally different chemical substances. The
capacity to metabolize and detoxify a wide
range of chemical substances is considerable.
However, the enzyme activities of phase I and
phase II must be well coordinated, since toxic
intermediates with undesirable side effects occasionally
arise in the initial stages of phase II.
enzymes (mixed monooxygenases).
They represent the first phase of detoxification:
a substrate (RH) is oxidized to ROH utilizing atmospheric
oxygen (O2), with water (H2O) being
formed as a byproduct. A reductase delivers hydrogen
ions (H+) either from NADPH or NADH. A
characteristic feature of P450 enzymes (2) is
that a single chemical substrate can frequently
be degraded by several P450 enzymes and that
a single P450 protein can oxidize a number of
structurally different chemical substances. The
capacity to metabolize and detoxify a wide
range of chemical substances is considerable.
However, the enzyme activities of phase I and
phase II must be well coordinated, since toxic
intermediates with undesirable side effects occasionally
arise in the initial stages of phase II.
Debrisoquin metabolism
Debrisoquin is an isoquinoline-carboxamidine.
It was used to treat high blood pressure until it
was found to cause severe side effects in 5–10%
of the population. These persons have reduced
activity of a degrading enzyme, debrisoquin-4-
hydroxylase. A number of other medications,
including !-adrenergic blockers, antiarrhythmics,
and antidepressives, are also degraded by
this enzyme and may also cause untoward reactions
in persons with low activity. Individuals
with a slow rate of degradation show an increased
ratio of debrisoquin/4-hydrodebrisoquin
(1). The enzyme is coded for by the 450-
db1 gene, a member of the cytochrome P450-
IID family (CYP2D). Mutations may cause aberrant
splicing and produce a variant pre-mRNA
containing an additional intron
It was used to treat high blood pressure until it
was found to cause severe side effects in 5–10%
of the population. These persons have reduced
activity of a degrading enzyme, debrisoquin-4-
hydroxylase. A number of other medications,
including !-adrenergic blockers, antiarrhythmics,
and antidepressives, are also degraded by
this enzyme and may also cause untoward reactions
in persons with low activity. Individuals
with a slow rate of degradation show an increased
ratio of debrisoquin/4-hydrodebrisoquin
(1). The enzyme is coded for by the 450-
db1 gene, a member of the cytochrome P450-
IID family (CYP2D). Mutations may cause aberrant
splicing and produce a variant pre-mRNA
containing an additional intron
CYP gene superfamily (cytochrome P450 genes)
The cytochrome P450 genes in mammals are
designated CYP genes. They make up a superfamily
of genes that resemble each other in
exon/intron structure and that code for similar
gene products. An evolutionary pedigree has
been derived based on comparisons of their
cDNA sequences. According to this pedigree,
the CYP gene family arose during the last 1500–
2000 million years. It is assumed that the CYP-2
family in particular developed in response to
toxic substances in plants that had to be detoxified
by animal organisms. At least 30 gene duplications
and gene conversions have led to an
unusually diverse repertoire of CYP genes.
designated CYP genes. They make up a superfamily
of genes that resemble each other in
exon/intron structure and that code for similar
gene products. An evolutionary pedigree has
been derived based on comparisons of their
cDNA sequences. According to this pedigree,
the CYP gene family arose during the last 1500–
2000 million years. It is assumed that the CYP-2
family in particular developed in response to
toxic substances in plants that had to be detoxified
by animal organisms. At least 30 gene duplications
and gene conversions have led to an
unusually diverse repertoire of CYP genes.
Pharmacogenetics
Many medications are degraded at different
rates in different individuals. This has a genetic
basis. Enzymes coded for by genes with different
alleles may have different catabolic rates,
which in turn can result in genetically determined
differences in the reaction to drugs
(pharmacogenetics).
rates in different individuals. This has a genetic
basis. Enzymes coded for by genes with different
alleles may have different catabolic rates,
which in turn can result in genetically determined
differences in the reaction to drugs
(pharmacogenetics).
Malignant hyperthermia due to abnormal regulation of a calcium channel in muscle cells
Malignant hyperthermia is a severe, lifethreatening
complication of anesthesia that
may occur in persons with extreme hypersensitivity
to halothane and similar agents used in
general anesthesia. Normally, a nerve impulse
depolarizes the plasma membrane of a nerve
ending at the nerve–muscle endplate (1)
(motor endplate), and the volt-gated calcium
channel in the plasma membrane of the nerve
ending is temporarily opened. The massive influx
of calcium into the cell (the extracellular
Ca2 + concentration is about 1000 times higher
than the intracellular) triggers the release of
acetylcholine. Binding of the latter to the acetylcholine
receptor of the muscle cell temporarily
opens the receptor-controlled cation (Na+)
channels. This opens calcium channels located
in the sarcoplasmic reticulum of the muscle
cell. The resulting rapid increase in Ca2 +
concentration in the cytosol causes the myofibrils
in the muscle cell to contract. The calcium
channels in the sarcoplasmic reticulum are
regulated by a receptor (ryanodin receptor) (2).
Ryanodin (an alkaloid) binds to the calcium
channel. The ryanodin receptor is a protein with
four transmembrane domains. Mutations in the
ryanodin receptor lead to greatly increased sensitivity
to halothane and other anesthetic
agents (3), which cause muscle spasm, drastic
elevation of temperature (hyperthermia), acidosis,
and cardiac arrest (4). Malignant hyperthermia
is inherited as an autosomal dominant
trait (5). One gene in man lies on chromosome
19 at 19q13.1 (MacLennan and Phillips, 1992).
Additional loci are on 7q, 17q, and 3q13.1 (Subrak
et al., 1995). The mutant haplotype of a
given family can be determined by segregation
analysis. A ryanodin receptor mutation has
been demonstrated in porcine malignant hyperthermia.
complication of anesthesia that
may occur in persons with extreme hypersensitivity
to halothane and similar agents used in
general anesthesia. Normally, a nerve impulse
depolarizes the plasma membrane of a nerve
ending at the nerve–muscle endplate (1)
(motor endplate), and the volt-gated calcium
channel in the plasma membrane of the nerve
ending is temporarily opened. The massive influx
of calcium into the cell (the extracellular
Ca2 + concentration is about 1000 times higher
than the intracellular) triggers the release of
acetylcholine. Binding of the latter to the acetylcholine
receptor of the muscle cell temporarily
opens the receptor-controlled cation (Na+)
channels. This opens calcium channels located
in the sarcoplasmic reticulum of the muscle
cell. The resulting rapid increase in Ca2 +
concentration in the cytosol causes the myofibrils
in the muscle cell to contract. The calcium
channels in the sarcoplasmic reticulum are
regulated by a receptor (ryanodin receptor) (2).
Ryanodin (an alkaloid) binds to the calcium
channel. The ryanodin receptor is a protein with
four transmembrane domains. Mutations in the
ryanodin receptor lead to greatly increased sensitivity
to halothane and other anesthetic
agents (3), which cause muscle spasm, drastic
elevation of temperature (hyperthermia), acidosis,
and cardiac arrest (4). Malignant hyperthermia
is inherited as an autosomal dominant
trait (5). One gene in man lies on chromosome
19 at 19q13.1 (MacLennan and Phillips, 1992).
Additional loci are on 7q, 17q, and 3q13.1 (Subrak
et al., 1995). The mutant haplotype of a
given family can be determined by segregation
analysis. A ryanodin receptor mutation has
been demonstrated in porcine malignant hyperthermia.
Serum pseudocholinesterase
deficiency (butyrylcholinesterase)
About 1 in 200 individuals reacts to muscle relaxants,
such as suxamethonium (succinylcholine),
with prolonged muscle relaxation and
respiratory arrest. In such persons, serum pseudocholinesterase
activity is decreased. Persons
at risk cannot be identified by determining their
pseudocholinesterase activity alone (1), but by
determining dibucaine inhibition of their
enzyme activity. Whereas homozygous normal
persons show 80% enzyme activity after dibucaine
administration, persons at risk show only
20%. Individuals with intermediate values of
60% are regarded as heterozygotes (2). A number
of different alleles can lead to different
degrees of reduced enzyme activity. (Figure
after Harris, 1975.) This enzyme is now referred
to as butyrylcholinesterase because it hydrolyzes
butyrylcholine more readily than acetylcholine.
About 1 in 200 individuals reacts to muscle relaxants,
such as suxamethonium (succinylcholine),
with prolonged muscle relaxation and
respiratory arrest. In such persons, serum pseudocholinesterase
activity is decreased. Persons
at risk cannot be identified by determining their
pseudocholinesterase activity alone (1), but by
determining dibucaine inhibition of their
enzyme activity. Whereas homozygous normal
persons show 80% enzyme activity after dibucaine
administration, persons at risk show only
20%. Individuals with intermediate values of
60% are regarded as heterozygotes (2). A number
of different alleles can lead to different
degrees of reduced enzyme activity. (Figure
after Harris, 1975.) This enzyme is now referred
to as butyrylcholinesterase because it hydrolyzes
butyrylcholine more readily than acetylcholine.
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