TY - JOUR
T1 - Effects of cytochrome p450 inducers on i-compounds in rat liver and kidney dna
AU - Li, Donghui
AU - Moorthy, Bhagavatula
AU - Chen, Shuo
AU - Randerath, Kurt
N1 - Funding Information:
This work was supported by US Public Health Service grants R37 CA32157 and P42 ESO4917 awarded by the National Cancer Institute and the National Institute of Environmental Health Sciences respectively.
PY - 1992/7
Y1 - 1992/7
N2 - I-compounds are covalent DNA modifications presumably derived from endogenous electrophiles. To investigate the possible role of cytochrome P450 in I-compound metabolism, groups of female Sprague-Dawley rats (225-250 g) were treated i.p. with vehicle or cytochrome P450 inducers, i.e. 80 mg/kg phenobarbital (PB), 20 mg/kg 3-methylcholanthrene (MC) or 50 mg/kg pregnenolone-l6α-carbonitrile (PCN), once daily for 4 days. DNA synthesis rate was measured via [3H]methylthymidine incorporation. DNA adducts and I-compounds in liver and kidney were analyzed 1 and 8 days after the last treatment. Total liver and kidney microsomal cytochrome P450 content and activities of representative drug-metabolizing enzymes for PB, MC and PCN, i.e. benzphetamine N-demethylase, ethoxycoumarin O-deethylase (ECD) and erythromycin N-demethylase, were also determined in all groups. PCN caused significant depletion of total non-polar I-compounds at 1 day, compared to controls. Levels of several Individual I-spots in liver were differentially reduced by each of the three inducers at 1 day. Most I-spots were restored to control levels at 8 days. Kidney I-compounds were not affected by PB or PCN, but MC reduced the level of one non-polar individual I-compound at 1 day. Except for the expected DNA adduct fonnation from MC, there were no qualitative changes in profiles of postlabeled modified nucleotides. Total cytochrome P450 content in liver microsomes and activities of individual P450 enzymes were significantly increased by treatment with each of the inducers at 1 day. This was, however, not the case at 8 days in PB- and PCN-treated livers. MC-treated rats, on the other hand, displayed elevated levels of liver cytochrome P450 and ECD at 8 days. In kidney, PB and PCN did not elicit induction of P450 and individual enzymes, but MC increased total P450 content and ECD activity at 1 day, and ECD activity alone at 8 days. These results suggest a major role for cytochrome P450 enzymes in the metabolism of I-compounds.
AB - I-compounds are covalent DNA modifications presumably derived from endogenous electrophiles. To investigate the possible role of cytochrome P450 in I-compound metabolism, groups of female Sprague-Dawley rats (225-250 g) were treated i.p. with vehicle or cytochrome P450 inducers, i.e. 80 mg/kg phenobarbital (PB), 20 mg/kg 3-methylcholanthrene (MC) or 50 mg/kg pregnenolone-l6α-carbonitrile (PCN), once daily for 4 days. DNA synthesis rate was measured via [3H]methylthymidine incorporation. DNA adducts and I-compounds in liver and kidney were analyzed 1 and 8 days after the last treatment. Total liver and kidney microsomal cytochrome P450 content and activities of representative drug-metabolizing enzymes for PB, MC and PCN, i.e. benzphetamine N-demethylase, ethoxycoumarin O-deethylase (ECD) and erythromycin N-demethylase, were also determined in all groups. PCN caused significant depletion of total non-polar I-compounds at 1 day, compared to controls. Levels of several Individual I-spots in liver were differentially reduced by each of the three inducers at 1 day. Most I-spots were restored to control levels at 8 days. Kidney I-compounds were not affected by PB or PCN, but MC reduced the level of one non-polar individual I-compound at 1 day. Except for the expected DNA adduct fonnation from MC, there were no qualitative changes in profiles of postlabeled modified nucleotides. Total cytochrome P450 content in liver microsomes and activities of individual P450 enzymes were significantly increased by treatment with each of the inducers at 1 day. This was, however, not the case at 8 days in PB- and PCN-treated livers. MC-treated rats, on the other hand, displayed elevated levels of liver cytochrome P450 and ECD at 8 days. In kidney, PB and PCN did not elicit induction of P450 and individual enzymes, but MC increased total P450 content and ECD activity at 1 day, and ECD activity alone at 8 days. These results suggest a major role for cytochrome P450 enzymes in the metabolism of I-compounds.
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U2 - 10.1093/carcin/13.7.1191
DO - 10.1093/carcin/13.7.1191
M3 - Comment/debate
C2 - 1638686
AN - SCOPUS:0026651010
SN - 0143-3334
VL - 13
SP - 1191
EP - 1198
JO - Carcinogenesis
JF - Carcinogenesis
IS - 7
ER -