MAP Technical Reports Series No. 106 UNEP

7.2.2.9 Mechanism of action
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Okadaic acid, being hydrophobic (Shibata et al., 1982), can enter cells and operate on
particulate as well as cytosolic fraction of various mouse tissues (Suganuma et al., 1989). It is
a very potent inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), two
of the four major protein phosphatases in the cytosol of mammalian cells that dephosphorylate
serine and threonine residues (Hescheler et al., 1988; Cohen, 1989). Of the other two major
protein phosphatases, the Ca 2+ /calmodulin-dependent protein phosphatase 2B (PP2B) is far
less sensitive, while the Mg 2+ -dependent protein phosphatase 2C (PP2C) is unaffected (Bialojan
et al., 1988). Okadaic acid probably causes diarrhoea by stimulating the phosphorylation that
controls sodium secretion by intestinal cells as in the disease cholera caused by a toxin
secreted by Vibrio cholerae, but with another mechanism. One of the subunits of cholera toxin
can permanently activate the Gs protein, leading to continuous adenylate cyclase activity
(Johnson, 1982). The resulting increase in cAMP activates cAMP-dependent protein kinase,
which then phosphorylates one or more proteins that control sodium secretion by intestinal cells.
Since cAMP or Ca 2+ /calmodulin dependent protein kinases or protein kinase C (Terao et al.,
1986; Takai et al., 1987; Haystead et al., 1989) are unaffected by okadaic acid, the inhibition of
PP1 and PP2 is probably responsible for phosphorylate control of ion channels (Kume et al.,
1989).
Recent data indicate that okadaic acid may function, not only as tumor promoter, but
it is also capable of reversing cell transformation by some oncogenes. It was found, employing
the two-stage carcinogenesis model, that okadaic acid (Suganuma et al., 1988) and DTX-1
(Fujiki et al., 1988) acted as promoter of skin tumors in the mouse, using dimethylbenz(a)anthracene
(DMBA) as tumor initiator. Whether this implies a risk for human health, it
remains to be clarified (Hall, 1991). In addition NIH3T3 cells transformed by either the raf or ret-II
oncogenes partially revert to the normal phenotype after incubation for two days with 10 nM
okadaic acid (Sakai et al., 1989).
7.2.2.10 Therapeutical notes
Fluid secretion (diarrhoea) occurs in patients with DSP. The secretory state is a result
of okadaic acid and DTX1 biotoxins which probably stimulate the phosphorylation that controls
sodium secretion by intestinal cells.
The luminal plasma membrane contains a transport system that facilitates a tightly
coupled movement of Na + and D-glucose (or structurally similar sugars) which is not regulated
by protein kinase. Modern oral treatment of cholera takes advantage of the presence of Na + -
glucose cotransport in the intestine. In this case, the presence of glucose allows uptake of Na +
to replenish body NaCl. Composition of solution for oral treatment of cholera patients is 110 mM
glucose, 99 mM Na + , 74 mM Cl - , 39 mM HCO 3 - , and 4 mM K + (Carpenter, 1980). A similar oral
treatment in DSP could be experimented.
7.2.2.11 Tolerance levels and remarks on safety
The established tolerances vary greatly from country to country since no evaluation of
DSP tolerances has yet been made by international organizations, like the World Health
Organization (Krogh, 1989). In the interim before issue of these definitions a surveillance plan
for DSP has been introduced in several European countries and also in Italy comprising the
analysis of seawater of phytoplankton and shellfish for detection of Dinophysis spp. in digestive
tract as well as for toxin analysis (Krogh, 1989; Ministero della Sanità, 1990 a,b,c). A number of
EC countries have established tolerances for DSP, applicable for domestic