DNA fragmentation in some organs of rats and mice treated with cycasin

Abstract

Summary.-Cycasin (methylazoxymethanol-p-D-glucoside) is carcinogenic in several animal species. It produces a variety of malignant tumours, mainly in the liver of mice, and in the liver, kidney and large intestine in rats. It does not appear to be mutagenic in the Ames test, even in the presence of liver microsome fraction, and it is among those carcinogens (less than 10%) ranked as "false negatives" in this test. The ability of cycasin to damage in vivo liver, kidney, lung and colonic DNA of Wistar rats and C57BL/6 mice was investigated by means of alkaline elution technique. Oral single-dose administration of cycasin, in the range of 50-400 mg/kg body weight, produced in the rat a clearly evident dose-dependent DNA fragmentation in the liver, and less marked damage to DNA from kidney and colon mucosa. In mice, the same treatment produced dose-dependent DNA damage only in the liver. DNA repair up to 18 h appeared to be incomplete both in mice and rats. Methylazoxymethanol acetate is considered to be an active form of cycasin. While in vivo methylazoxymethanol acetate caused DNA damage, in vitro it appeared inactive and required metabolic activation, possibly consisting in its hydrolysis by esterase activity, to be able to cause DNA fragmentation.CYCASIN (methylazoxymethanol-,B-Dglucoside), which occurs in cycad plants used by some populations as food, has been reported to be carcinogenic in rodents (mice, rats, hamsters, guinea-pigs and rabbits) (IARC, 1976 Brambilla et al., 1978). A ranking tabulation of doserelated DNA damage induced by cyeasin in rats has been preliminarily reported . MATERIALS AND METHODSIn these experiments C57BL/6 male mice and Wistar male rats, aged 1-2 months, were used. Cycasin (a gift from Dr H. Matsumoto, University of Hawaii at Manoa, Honolulu) was dissolved in distilled water and administered orally by gastric intubation at varying single-dose levels and intervals before animals were killed by cervical dislocation and exsanguinated. Methylazoxymethanol acetate (ICN Pharmaceuticals, Inc., Plainview, New York, U.S.A.) was dissolved in physiological saline and injected i.p. into C57BL/6 male mice. Liver, kidneys, lungs and descending colon were quickly removed and rinsed in

Damage and Repair of Nerve Cell Dna in Toxic Stress*

“…5. N 7 -Methylguanine, the major DNA adduct produced by MAM, accumulates preferentially with age in postmitotic rat brain and liver cells [79,97] and is found in fetal [98] and, presumably, adult [67] brain and liver [92] tissue of rats treated prenatally or postnatally with MAM, respectively. Normal repair of damaged neuronal DNA, which may be disturbed by cycad toxins, appears to be essential for maintaining the integrity of the human nervous system [99].…”

Induction of sister chromatid exchange in multiple murine tissues in vivo by various methylating agents

“…MAM, which exhibits organospecificity for tumor formation similar to DMH and DMN [32,33], was not an effective inducer of SCE in vivo in any of the tissues examined. Hydrolysis is required in order for MAM to produce DNA damage [34]. A study by Thust et a1 [35] demonstrated a loss of SCEinducing activity in a host-mediated assay when MNU is administered i.v.…”

Food-Borne Chemical Carcinogens and the Evidence for Human Cancer Risk

“…Genotoxicity/DNA Binding (Adducts) : Cycasin was genotoxic after removal of a sugar residue to yield the aglycone, MAM, which is an alkylating agent [ 89 , 169 , 170 , 171 , 172 , 173 ]. MAM produced DNA adducts, specifically O 6 -methylguanine and N 7-methylguanine, in vitro and in vivo in rats and guinea pigs [ 174 , 175 , 176 , 177 , 178 ].…”