| Autor: |
Babu, Satram R., Lakshmi, Vijaya M., Hsu, F. F., Zenser, Terry V., Davis, Bernard B. |
| Zdroj: |
Carcinogenesis; 1995, Vol. 16 Issue 12, p3069-3074, 6p |
| Abstrakt: |
Glucuronidation of -hydroxy arylamines is thought to be a necessary step in their initiation of bladder cancer. This was evaluated for the -hydroxy metabolites of -acetylbenzidine (ABZ). '-Hydroxy--acetylbenzidine (-HA), -hydroxy--acetylbenzidine (-HA) and -hydroxy-,'-diacetylbenzidine (-HDA) were synthesized. Except for '-HA, these compounds were quite stable. Ascorbic acid and/or acidic pH increased the stability of '-HA. When each -hydroxy compound was added to reaction mixtures containing [C]UDP-glucuronic acid, 3 mM ascorbic acid and human liver microsomes a new product was detected by HPLC. Emulgen 911 was a better detergent than Triton X-100 for expressing microsomal activity, with maximal glucuronidation observed with 0.3% Emulgen 911. At 0.125 mM amine the rate of glucuronidation was -HDA >> ′-HA = benzidine > ABZ > -HA. In contrast, at 0.5 mM amine the rate of glucuronidation of -HA was only exceeded by -HDA. At pH 5.5 and 37°C the for the enzymatically prepared glucuronide conjugates of ABZ, ′-HA and -HA were 7.5 min and 3.5 and 1.8 h respectively. For -HDA >90% of this glucuronide remained after 24 h. At pH 7.4 and 37°C the for the glucuronide conjugates of ABZ and -HA were 2.3 and 2 h respectively, with the amounts remaining after 24 h for ′-HA and -HDA being 75 and 90% respectively. At pH 6.5 the for ′-HA was 14 h. Thus only glucuron-ides of ABZ and ′-HA exhibit pH-dependent changes in . Compared with ABZ, glucuronides the -hydroxy metabolites are more stable at acidic pH. Acidic urine would be more likely to hydrolyze the glucuronide conjugate of ABZ than those of its -hydroxy metabolites. Because these results are different from that hypothesized for arylmonoamines, a new model was developed to explain the role of -oxidation, -glucuronidation and -acetylation in the carcinogenesis of benzidine, an aryldiamine. [ABSTRACT FROM PUBLISHER] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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