Abstract:
:Dihydrodiol dehydrogenase (DD) has been shown to catalyze the oxidation of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo [a]pyrene (BP-diol) to yield benzo[a]pyrene-7,8-dione (BPQ) in uninduced fortified rat liver S100 fractions but the formation of BPQ has not been observed in whole cells. In these studies [3H]BP-diol was incubated with isolated hepatocytes from uninduced rats for 0-20 min at 37 degrees C. Organic-extractable radioactivity in the cell media accounted for 20% of the total [3H]BP-diol added. Reverse phase (RP)-HPLC analysis of this fraction revealed the formation of an unknown metabolite that co-chromatographed with an authentic synthetic standard of BPQ. The identity of the unknown metabolite was further established by: (i) co-chromatography with synthetic BPQ under both RP- and normal phase-HPLC conditions using diode array detection, which indicated that metabolite shared UV/vis spectral identity with standard BPQ; and by (ii) electron impact mass spectrometry of the unknown metabolite which gave the same parent and fragment ions as the synthetic standard. The formation of BPQ by isolated hepatocytes was found to be 0.50 nmol/3 x 10(6) cells/10 min, and represented 7% of the total organic-soluble metabolites in the extracellular media. Its formation was abolished by the addition of indomethacin, a competitive inhibitor of DD, indicating that this enzyme was responsible for BPQ formation. Other organic-soluble metabolites formed corresponded to BP-tetraols (hydrolysis products of the anti- and syn-diol epoxides). Examination of the aqueous phase of the extracellular media indicated that a large portion of BP-diol was converted to glucuronide and sulfate conjugates. Under the conditions employed BP-tetraols and BPQ were formed to an equal extent implying that in hepatocytes isolated from uninduced rats, DD and CYP1A1 contributed equally to the metabolism of BP-diol.
journal_name
Carcinogenesisjournal_title
Carcinogenesisauthors
Flowers-Geary L,Harvey RG,Penning TMdoi
10.1093/carcin/16.11.2707subject
Has Abstractpub_date
1995-11-01 00:00:00pages
2707-15issue
11eissn
0143-3334issn
1460-2180journal_volume
16pub_type
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