Abstract:
:The extent to which N-acetylbenzidine and N,N'-diacetylbenzidine are formed may influence benzidine-induced carcinogenesis. This study compared the formation of these metabolites by rat and human liver slices. The relationship between the NAT2 genotype and the formation of these acetylated products was also evaluated in humans. In rat liver slices incubated with 0.05 mM [3H]benzidine for 1 h (n = 3), N-acetylbenzidine and N,N'-diacetylbenzidine represented 8.8 +/- 3.6 and 73 +/- 2.5% respectively of the total radioactivity recovered by HPLC. No unmetabolized benzidine was observed. This suggests that an equilibrium exists between benzidine, N-acetylbenzidine and N,N'-diacetylbenzidine in rat liver slice incubations which favors N,N'-diacetylbenzidine formation. In the presence of 0.1 mM paraoxon, a deacetylase inhibitor, N-acetylbenzidine and N,N'-diacetylbenzidine increased to 13 +/- 0.6 and 79 +/- 0.3% respectively. Within 2 h after incubating human liver slices with 0.014 mM [3H]benzidine (n = 8), benzidine, N-acetylbenzidine and N,N'-diacetylbenzidine represented 19 +/- 5, 34 +/- 4 and 1.6 +/- 0.5%, respectively, of the total radioactivity recovered by HPLC. Thus in the human, conditions in liver slices favor N-acetylbenzidine rather than N,N'-diacetylbenzidine formation. With paraoxon, benzidine, N-acetylbenzidine and N,N'-diacetylbenzidine represented 2 +/- 0.4, 24 +/- 4 and 51 +/- 3%, respectively. This resulted in a 32-fold increase in N,N'-diacetylbenzidine formation. Individuals with rapid NAT2 genotypes formed 1.4-fold more N-acetylbenzidine than slow acetylators. However, this increase was not significant. There was no apparent correlation of N,N'-diacetylbenzidine formation with NAT2 genotype. Similar results were observed when human slices were incubated with 0.09 mM [3H]benzidine. Deacetylase, perhaps more than N-acetyltransferase, influences hepatic metabolism and subsequent carcinogenesis of benzidine in man. These results help explain the species and organ specificity of benzidine carcinogenesis.
journal_name
Carcinogenesisjournal_title
Carcinogenesisauthors
Lakshmi VM,Bell DA,Watson MA,Zenser TV,Davis BBdoi
10.1093/carcin/16.7.1565subject
Has Abstractpub_date
1995-07-01 00:00:00pages
1565-71issue
7eissn
0143-3334issn
1460-2180journal_volume
16pub_type
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