Abstract:
:The purpose of this study was to compare the metabolism and DNA binding of aflatoxicol (AFL) with that of aflatoxin B1 (AFB1) in vivo and in isolated hepatocytes from Mt Shasta strain rainbow trout (Salmo gairdneri). Maximum total binding of [3H]AFL to liver DNA from trout exposed by intraperitoneal injection was 38-47% of that of [3H]AFB1 over a 1-7 day period. The average AFL/AFB1 DNA binding ratio in 1-h incubations with isolated hepatocytes was 0.67 +/- 0.36 (n = 13). In freshly isolated hepatocytes, substantial interconversion between AFB1 and AFL via reductase and dehydrogenase enzymes was observed. Total in vivo excretion of conjugates in bile over 4 days was greater for [3H]AFL substrate than for [3H]AFB1. To determine if AFL binding was due to direct activation or to prior metabolism to AFB1 followed by activation, AFL with a tritium atom on the carbon containing the cyclopentenol function [1-3H]AFL, was synthesized and incubated with hepatocytes. Binding of [1-3H]AFL was 3% that of [3H]AFB1 and represents only direct binding of the intact cyclopentenol epoxide molecule before transformation to AFB1 and consequent loss of 3H. H.p.l.c. analysis of DNA hydrolyzed after incubation with [1-3H]AFL resulted primarily in production of non-radioactive 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-guanine). A radioactive peak estimated to be 1% as abundant as the AFB1-N7-guanine was also observed. The overall binding of generally labeled [3H]AFL to trout liver DNA in vivo and in freshly prepared hepatocytes correlates well with available tumor incidence and mutagenicity data. Conclusions from these findings are that direct interaction of AFL-8,9-epoxide with DNA is of relatively minor quantitative importance in rainbow trout hepatocytes and that the major adduct results from conversion of AFL to AFB1 prior to epoxide formation.
journal_name
Carcinogenesisjournal_title
Carcinogenesisauthors
Loveland PM,Wilcox JS,Pawlowski NE,Bailey GSdoi
10.1093/carcin/8.8.1065subject
Has Abstractpub_date
1987-08-01 00:00:00pages
1065-70issue
8eissn
0143-3334issn
1460-2180journal_volume
8pub_type
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