Chemical structure- and time-dependent effects of polycyclic aromatic hydrocarbon-type inducers on rat liver cytochrome P450, DNA adducts, and I-compounds.
It is well documented that cytochrome P450IA1 (CYP1A1) plays an important role in carcinogen activation. CYP1A1/1A2 induction may serve as a biomarker of exposure to environmental toxins. In order to explore a specific role of CYP1A1 in metabolism of I-compounds (age-dependent indigenous DNA modifications), 2-month-old female Sprague-Dawley rats were treated ip with corn oil (2 ml/kg) or with one of several CYP1A1 inducers, i.e., dibenz[a,c]anthracene (DBA) (93 mumol/kg), benzo[a]pyrene (BP) (93 mumol/kg), naphthacene (NAP) (93 mumol/kg), or beta-naphthoflavone (BNF) (140 mumol/kg), once daily for 4 days. Levels of total cytochrome P450 and activities of CYP1A1-associated enzymes, i.e., ethoxycoumarin O-deethylase (ECD) and ethoxyresorufin O-deethylase (EROD), were determined in liver microsomes at 1, 8, or 15 days after the last treatment. DNA adducts and I-compounds were analyzed by nuclease P1-enhanced 32P-postlabeling. DNA synthesis rate was determined by measuring [3H]methylthymidine incorporation into DNA. Each inducer significantly elevated the total P450 level at 1 day. The enzyme levels in BP-, NAP-, and BNF-treated animals gradually returned to control by 8 and 15 days, but elevated levels persisted in DBA-treated rats. Similar trends were observed for ECD and EROD activities. DBA and BP, but not NAP and BNF, gave rise to several measurable DNA adducts, which persisted throughout the period of study. All P450 inducers, irrespective of adduct formation, strongly depleted both nonpolar and polar I-compounds, the effects being most pronounced at 1 and 8 days. These results imply a specific role for CYP1A1 in the regulation of I-compound metabolism, in addition to PAH activation.
Moorthy
B
B
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030.
Sriram
P
P
Randerath
K
K
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D011083:Polycyclic Compounds / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013997:Time Factors
D011083:Polycyclic Compounds; D004247:DNA; D003577:Cytochrome P-450 Enzyme System