trans

334 HELMINTH SURFACES
in the hypodermis. Fourteen pgp-encoding
genes have been identified in C. elegans, some
of which are probably pseudogenes. Deletion
of two of these genes leads to increased susceptibility
to chloroquine, colchicine and to
heavy metals that are not toxic to wild-type
C. elegans. To this point, however, no C. elegans
anthelmintic-resistance trait has been mapped
to a pgp locus.
The animal-parasitic nematode H. contortus
expresses at least four pgp genes. In some
strains, a pgp polymorphism is associated with
macrocyclic lactone resistance. These observations,
however, do not establish a causal link
between pgp polymorphism and anthelmintic
resistance. Resistant and sensitive strains of
H. contortus do not absorb these drugs at different
rates, or accumulate them in specific worm
tissues in a different manner. Ascribing a role
for pgps in anthelmintic resistance will require
demonstrating that pgp-deficient strains accumulate
drugs more rapidly, or that pgp overexpressing
strains accumulate drugs more slowly,
than wild types. In this context, a closantelresistant
strain of H. contortus accumulates
closantel less rapidly than wild-type strains.
Closantel, like ivermectin, is highly lipophilic,
which is a hallmark of most substrates for pgps.
However, no pgp polymorphism has been associated
with the closantel-resistant phenotype.
Because these experiments only tracked variation
in a limited number of restriction sites, the
findings cannot rule out pgp involvement in
closantel resistance.
Whether or not alterations in pgp expression
or sequence have been selected as a mechanism
of anthelmintic resistance, there is ample
evidence to conclude that these proteins contribute
to the excretion behavior of nematodes.
Their primary location in intestinal cells is
consistent with a role in eliminating compounds
that penetrate the cuticle, diffuse
through worm tissue and accumulate in PCF.
ATP-dependent transport of xenobiotics from
PCF to the intestinal lumen would reduce internal
drug levels and protect the organism from
toxicity.
Defecation
Most adult nematodes defecate. Studies in
C. elegans have illuminated the physiology
and genetics of defecation, a rhythmic, patterned
behavior that is controlled by the availability
and quality of food. Transit of fecal
material through the intestinal tract is rapid;
the default defecation cycle in C. elegans is
45 seconds. A Ca 2 spike in posterior regions of
the intestine precedes and probably initiates
the first phase of defecation, referred to as the
posterior body-wall contraction. Mutations in
aex-2, which encodes a G-protein-coupled
receptor expressed in the intestinal muscles
NSM and AWB, result in defects in this response.
Though the signaling mechanism that underlies
this response has not been determined,
available evidence suggests that it is peptidergic,
as mutations in two enzymes, aex-5 and
egl-21, which process small neuropeptides,
also produce the Aex phenotype.
Less is known about defecation in parasitic
species. The contents of the gut in A. suum are
turned over every three minutes, and defecation
can propel fecal material up to 60 cm. The
major muscle groups that regulate defecation
(pharynx and rectum) are innervated, and it is
likely that the nervous system plays a critical
role in this process, as shown for C. elegans.
However, not all nematodes possess a functional
one-way gut, and defecation may be
less important in these species. The extent to
which the gut is functional in adult female
O. volvulus is an open question. It appears that
adults of this species, and perhaps other filariae,
both acquire nutrients and excrete waste
products across the cuticle–hypodermis complex.
Though it would seem a simple matter to
BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS