N-acetylbenzidine and N,N'-diacetylbenzidine formation by rat and human liver slices exposed to benzidine.

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

Carcinogenesis

journal_title

Carcinogenesis

authors

Lakshmi VM,Bell DA,Watson MA,Zenser TV,Davis BB

doi

10.1093/carcin/16.7.1565

subject

Has Abstract

pub_date

1995-07-01 00:00:00

pages

1565-71

issue

7

eissn

0143-3334

issn

1460-2180

journal_volume

16

pub_type

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