Sex-specific modulation of hepatic covalent DNA modifications (I-compounds) by the cytochrome P450 inducer, pregnenolone-16 alpha-carbonitrile.
I-compounds are recently discovered, age-dependent covalent DNA modifications, which are detectable by 32P-postlabeling assay for DNA adducts. The effects of the catatoxic antiglucocorticoid, pregnenolone-16 alpha-carbonitrile (PCN), on hepatic and renal I-compound levels have been studied in male and female Sprague-Dawley rats together with the levels of microsomal cytochrome P450 and rates of ethylmorphine N-demethylation. PCN (50 mg/kg ip) was dissolved in corn oil and administered to rats once daily for 4 days, and animals were killed at 1 day or 8 days after the last treatment. Hepatic and renal I-compounds were analyzed by 32P-postlabeling in control and PCN-treated animals at both time points. Microsomal cytochrome P450 and ethylmorphine N-demethylase activities were also determined. Total levels of liver nonpolar and polar I-compounds were reduced in female rats by 37 and 51%, respectively, compared to controls, at 1 day. Ten out of sixteen individual I-compounds were also markedly reduced in female rat liver DNA as a result of PCN administration. In contrast to females, total levels of liver I-compounds were not significantly altered in males by PCN at 1 day; however, two individual I-compounds were lowered. I-compound levels recovered 8 days after termination of PCN treatment in both males and females. Total levels of renal I-compounds were not affected by PCN treatment in either males or females. [3H]Methylthymidine incorporation studies showed an increase in mean DNA synthesis rate at 1 day in liver of both males and females, but this was significant in males only. Marked induction of hepatic microsomal cytochrome P450 (2.2-fold) and ethylmorphine N-demethylase (4.0-fold) activity was observed in female rats treated with PCN at 1 day as compared to controls. The extent of induction of these enzymes was much higher in females than males. At 8 days the levels of cytochrome P450 and ethylmorphine N-demethylase activity had returned to uninduced values. The results are consistent with a pivotal role for PCN-inducible cytochrome P450 in the metabolism of I-compounds.
Moorthy
B
B
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030.
van Golen
K L
KL
Randerath
K
K
D000818:Animals; D001345:Autoradiography; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D013936:Thymidine / Q000378:metabolism
D011285:Pregnenolone Carbonitrile; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D013936:Thymidine