Biomedical subjects
Publications and source records attributed to Y H Chu.
Aflatoxin B1 reacts with poly(dC-dG) to form guanine adducts and apurinic sites. Such modification strongly inhibits the template capacity of the polynucleotide and leads to an increase in non-complementary nucleotide incorporation. The template inhibition and induced errors are reduced by mild heat depurination which removes all 7-substituted modifications.
The enhanced repair of O6-methylguanine from hepatic DNA in rats is a well established phenomenon that can be induced by pretreatment with a variety of hepatotoxic agents as well as by partial hepatectomy. Attempts to induce a similar hepatic response by treatment with single doses of aflatoxin B1 in C57Bl mice, single doses of dimethylnitrosamine (DMN) in C57Bl or BALB/C mice or by prolonged pretreatment with DMN by addition to the drinking water of C57Bl mice were uniformly unsuccessful. Furthermore, the intense proliferative response induced by two-thirds partial hepatectomy in C57Bl mice was also apparently incapable of increasing the activity of this repair function. These experiments, in which repair of O6-methylguanine has been determined both in vivo after administration of [14C]DMN and in vitro using crude tissue extracts and a methylated DNA substrate, indicate the presence of an intergeneric difference between rats and mice with respect to this repair function.
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Pretreatment of rats by the repeated administration of certain alkylating carcinogens has been shown to stimulate the removal of O6-alkylguanine from hepatic DNA. Prolonged feeding with the aromatic amide 2-acetylaminofluorene has a similar effect. In this report, aflatoxin B1, an agent from another chemically distinct class of carcinogen, is shown to be capable of stimulating the repair of O6-methylguanine in hepatic DNA. The sensitivity of this system is shown by the fact that this repair response can be fully stimulated as early as 1 day after treatment with a single dose.
Methylated purines were determined in the liver and kidney DNA of rats that had been pretreated for several weeks by inclusion of 2-acetylaminofluorene in the diet and then given single injections of N,N-dimethylnitrosamine. In comparison ith relevant controls the capacity to remove O(6)-methylguanine from the livers of the pretreated animals was enhanced but there was no evidence for a similar effect in kidney. No market effects of this pretreatment were observed for the removal of 3-methyladenine or 7-methylguanine. The data indicate that an inducing agent may affect the capacity of an animal to repair DNA which is subsequently damaged by another agent of chemically different identity. The mechanisms involved are not clear but potentially these observations have wide implications when organisms are exposed to a variety of chemicals.
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New transient kinetic methods, which allow kinetics to be carried out under conditions of excess substrate, have been employed to investigate the kinetics of hydride transfer from NADH to aromatic aldehydes and from aromatic alcohols to NAD+ as a function of pH. The hydride transfer rate from 4-deuterio-NADH to beta-naphthaldehyde is nearly pH independent from pH 6.0 to pH 9.9; the isotope effect is also pH independent with kappa-H/kappaD congruent to 2.3. Likewise, the rate of oxidation of benzyl alcohol by NAD+ changes little with pH between pH 8.75 and pH 5.9; the isotope effect for this process is between 3.0 and 4.4. Earlier substituent effect studies on the reduction of aromatic aldehydes were consistent with electrophilic catalysis by either zinc or a protonic acid. The pH independence of hydride transfer is consistent with electrophilic catalysis by zinc since such catalysis by protonic acid (with a pK between 6.0 and 10.0) would show strong pH dependence. However, protonic acid catalysis cannot be excluded if the pKa of the acid catalyst in the ternary NADH-E-RCOH complex were smaller than 6.0 or smaller than 10.0. The two kinetic parameters changing significantly with pH are the kinetic binding constant for ternary complex formation with aromatic alcohol and the rate of dissociation of aromatic alcohols from enzyme. This is consistent with base-catalyzed removal of a proton from alcohol substrated and consequent acid catalysis of protonation of a zinc-alcoholate complex. The equilibrium constant for hydride transfer from benzaldehyde to benzyl alcohol at pH 8.75 is K-eq equals kappa-H/kappa-H equals 42; this constant has important consequences concerning subunit interactions during liver alcohol dehydrogenase catalysis.
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