O⁶-Alkylguanine DNA alkyltransferase activity in monkey, human and rat liver

Abstract

Previous studies have shown that in in vitro assays using methylated DNA substrates, human and rat liver fractions were able to catalyse the repair of the promutagenic lesion O6-methylguanine (O6-meG). These studies have been extended to include monkey liver fractions and the repair of O6-ethylguanine (O6-etG). Human and monkey liver fractions have similar capacities for the repair of O6-meG and are 8-10 times more active than rat liver fractions. In all species examined, the liver extracts showed a lower capacity to repair O6-etG and the rate of repair was dependent on the degree of modification of the DNA substrate and the protein concentration used. The in vitro metabolism of dimethylnitrosamine (DMN), an alkylating carcinogen, by liver slices, has been previously demonstrated in these three species, but the activity in monkey liver was considerably lower compared with human and rat liver. The lack of evidence of a carcinogenic effect of DMN in the monkey liver could be correlated to this low capacity to metabolise DMN and the high O6-alkylguanine-DNA alkyltransferase levels in this organ.

N-nitrosodimethylamine-derived O6-methylguanine in DNA of monkey gastrointestinal and urogenital organs and enhancement by ethanol

“…The repair enzyme AGT was measured in many of these tissues in a separate monkey, and the results are given in the figure legends and Table I. The AGT values are in good agreement with those reported for comparable Macaca cynomolgus monkey and human tissues (Hall et al, 1985;Loktionova et al, 1993). Amounts of AGT varied over a 30-fold range in the monkey tissues.…”

O6-methylguanine-DNA methyltransferase protects against nitrosamine-induced hepatocarcinogenesis.

“…For example, carcinogenic N-alkyl-N-nitrosoureas are known to induce tumors preferentially in tissues with low MGMT activity (12)(13)(14)(15)(16), and upon exposure to ethylnitrosourea in vitro, rodent cell variants with low MGMT activity undergo malignant conversion with much higher frequency than their high MGMT activity counterpart cells (17). The presence ofMGMT proteins has been demonstrated in various organisms including bacteria, yeast, fish, rodents, monkeys, and humans (8,(18)(19)(20). The levels of MGMT activity vary greatly among species and also between tissues, the liver having the highest enzyme activity.…”

Repair of O-alkylpyrimidines in mammalian cells: a present consensus.

“…Both the m6-MT and the glycosylase are more efficient in acting on methyl derivatives than on ethyl derivatives (8)(9)(10). When 06-modified propyl-, butyl-, isopropyl-, or isobutyldeoxyguanosines are the substrates for m6-MT, the rate of dealkylation decreases with the size of the alkyl group, and the branched chain adducts are poorly repaired (11).…”