Abstract:
:The bioactivation of cyclopenta[cd]pyrene (CPP) was investigated to determine the major DNA adduct-forming metabolite(s) of this widespread environmental contaminant and suspect carcinogen. DNA adducts were analyzed by 32P-postlabeling. Four major and at least seven minor adducts formed when CPP was incubated with calf thymus DNA in the presence of rat liver microsomal systems. P450 subfamilies IA and IIB both activated CPP as microsomes from either phenobarbital- or beta-naphthoflavone-treated rats produced quantitatively similar and qualitatively identical adducts. When the epoxide hydrolase inhibitors, 1,1,1-trichloropropene-2,3-oxide or cyclohexene oxide were added to the incubations, binding increased 2.5- to 4-fold, suggesting epoxidation as a mechanism of adduct formation in vitro. Sprague-Dawley rats were killed 1, 3, 7, 18, 45 and 80 days postdosing i.p. with 50 mg/kg CPP. In all tissues analyzed, four major and several minor qualitatively identical adducts were produced. Binding was highest and most persistent in lung followed by heart, white blood cells (WBCs) and liver. CPP adducts were detectable at doses from 1 microgram/kg to 50 mg/kg. Rat lung DNA adducts were cochromatographed with standardized deoxyguanosine and deoxyadenosine adducts produced by reaction of CPP-3,4-epoxide in vitro. All rat lung adducts comigrated with the deoxyguanosine adducts but one was clearly deoxyadenosine derived. Mouse skin DNA adducts from NIH Swiss mice and mouse lung DNA adducts from B6C3F1 mice were also analyzed. All adducts from either mouse tissue comigrated with rat lung DNA adducts, suggesting CPP-3,4-epoxide was also the major DNA adduct-forming species in the mouse. CPP-3,4-epoxide has been suggested to be the key mediator of the biological activities of CPP. Evidence presented here strongly suggests CPP-3,4-epoxide as the major adduct-forming species of CPP as catalyzed in vitro by rat liver preparations known to mediate the mutagenic activation of CPP, in the rat in vivo, and in mouse skin and lung, two tissues with known sensitivity to CPP tumorigenicity.
journal_name
Carcinogenesisjournal_title
Carcinogenesisauthors
Beach AC,Gupta RCdoi
10.1093/carcin/15.5.1065subject
Has Abstractpub_date
1994-05-01 00:00:00pages
1065-72issue
5eissn
0143-3334issn
1460-2180journal_volume
15pub_type
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