CYANOBACTERIAL TOXINS - Cyanobacteria - page 523

SY5Y) is negligible. Inhibition of the uptake of 3 H-dihydromicrocystin-LR by bile acid transport
inhibitors (antamanide, 5 µM; sulfobromophthalein 50 µM and rifampicin 30 µM) indicates that the
MC-LR uptake is through multispecifi c transport system for bile acids (Eriksson et al. , 1990a). In
mice or rats the cause of death due to MC-LR was due to haemorrhagic shock secondary to massive
hepatocellular necrosis and collapse of hepatic parenchyma (Theiss et al ., 1988). The hepatocyte
deformation by MC-LR, 7-desmethyl-MC-RR and nodularin has been attributed to the increase in
overall level of protein phosphorylation (Eriksson et al ., 1990b). Robinson et al . (1991) conducted a
detailed study on the concentration of MC-LR given i.v. in liver. Though MC-LR concentration did
not change in liver but some portion of the toxin was excreted via urine and the faecal route. This
signifi es the role of liver in detoxifying MC-LR through the microsomal enzyme inducers (Brooks
and Codd, 1987). Kondo et al . (1996) identifi ed three metabolic products, i.e. a glutathione conjugate,
a cysteine conjugate and a conjugate with the oxidized Adda diene.
Sub-lethal doses of MC-LR (45 µg kg -1 body weight) were given to Bab/C mice and examined
after 2, 4, 12 and 24 h of exposure. Hepatocellular hypertrophy, eosinophilic cytoplasmic condensation
around the outer nuclear membrane and apoptosis of few hepatocytes were noted. Animals that
received two daily doses showed marked increase in apoptotic hepatocytes and those with four and
seven doses of the toxin showed hepatocytomegaly and karyomegaly (Guzman and Solter, 2002).
Nodularin selectively induced left lobe atrophy in livers of F344 rats but simulataneously right and
middle lobes increased in their weight. However, after three weeks of nodularin administration, when
diethylnitrosamine (DEN) was given for a total period of 10 weeks, DEN-altered hepatocytes regained
regenerating power with concomitant restoration of phosphatase activity (Lim et al ., 2001).
The LD 50 values of MC, nodularin and CYN have been determined by mouse bioassay. Most of
the structural variants of MCs and nodularins were toxic in the range 50-300 µg kg -1 body weight
(Table 3). Structural modifi cations of the Adda-glutamate region such as changes in isomerization
of Adda-diene (6(E) to 6(Z) or acylation of the glutamate yielded non-toxic derivatives of MCs and
nodularins (Harada et al ., 1990; Rinehart et al ., 1994). Accordingly, the LD 50 values for such variants
were found to be very high, i.e. 1000 to 1200 µg kg -1 body weight. The doses of MCs required i.p.
were 25-150 µg kg -1 body weight (Dawson, 1998; WHO, 1998). Concentrations for oral ingestions
were much higher, i.e. 5 to 10 mg kg -1 body weight (Ito et al ., 1997; WHO, 1998). On the other hand,
the inhalation toxicity of MC-LR is very high and the concentrations almost correspond to i.p. dose,
i.e. 36-122 µg kg -1 body weight (Dawson, 1998). The concentration of nodularin required for LD 50 is
50 µg kg -1 body weight given i.p. In case of CYN, the concentrations reported for LD 50 were 200-2000
µg kg -1 body weight administered i.p. (Chorus and Bartram, 1999). The concentrations of MCs with
lowest observed adverse effect level (LOAEL) and no observed adverse effect level (NOAEL) are
100 and 40 µg kg -1 body weight, respectively.
Oral administration of MC-LR (0, 40, 200 or 1000 µg kg -1 body weight for 13 weeks) in a good
laboratory practice on 15 male and female mice revealed NOAEL of 40 µg kg -1 body weight per day
(Fawell et al ., 1994). The LD 50 values for other forms of MCs are known to be 70 µg kg -1 body weight
(i.p. in mice) for MC-YR whereas MC-RR has an LD 50 (i.p. in mice) of 300-600 µg kg -1 body weight
(WHO, 2003). M . aeruginosa extract (containing at least seven variants of MCs of which MC-YR as
a major constituent) given to pigs i.p. at doses of 280, 800, 1310 µg kg -1 body weight per day in a
44 day study revealed LD 50 of nearly 100 µg. The LOAEL was found to be 280 µg kg -1 body weight
per day (Falconer et al ., 1994). On the other hand, a lethal dose of MC-LR for pigs was 72 µg kg -1
body weight given i.p. (Beasley et al ., 2000). Toxicity studies with MC-LR on embryonic and foetal
developmental studies in mice revealed a NOAEL of 600 µg kg -1 body weight per day (Fawell et al .,
1994). According to them MC-LR is not a selective developmental toxicant in mice.