Decreased liver cytochrome P-450 in rats caused by norethindrone or ethynyloestradiol

Abstract

19-Nor-17.alpha.-pregna-1,3,5(10)-trien-20-yne-3,17-diol (ethynylestradiol) or 17.beta.-hydroxy-19-nor-17.alpha.-pregn-4-en-20-yn-3-one (norethindrone) [constituents of some oral contraceptives] but not 17.alpha.-ethyl-17.beta.-hydroxy-19-norandrost-4-en-3-one (norethandrolone) caused a time-dependent loss of cytochrome P-450 when incubated in vitro with rat liver microsomal fractions and NADPH-generating systems. The enzyme system catalyzing the norethindrone-mediated loss of cytochrome P-450 had many characteristics of the microsomal mixed-function oxidases. It required NADPH and air, and was inhibited by CO. It was unaffected by 1 mM-compound SKF 525A [2-diethylaminoethyl 2,2-diphenylvalerate hydrochloride]. In microsomal fractions from phenobarbitone-pretreated rats the norethindrone-mediated loss of cytochrome P-450 was increased relative to controls. The norethindrone-mediated cytochrome P-450 loss was less pronounced when the animals were pretreated with 3.beta.-hydroxy-pregn-5-en-2-one 16.alpha.-carbonitrile (pregnenolone 16.alpha.-carbonitrile). Pretreatment with 3-methylcholanthrene rendered the animals resistant to the norethindrone effect. Administration in vivo [100 mg/kg, i.p.] of norethindrone or ethinylestradiol also produced a time-dependent loss of liver cytochrome P-450. Norethandrolone had a similar, though much less-marked, effect. All 3 steroids led to an induction of 5-aminolevulinate synthase and an accumulation of porphyrins in the liver. The loss of cytochrome P-450 and the accumulation of porphyrins in the liver 2 h after the administration of norethindrone to female rats was similar to that seen in males. Rats pretreated with phenobarbitone and given norethindrone or ethynylestradiol (100 mg/kg, i.p.) formed green pigments in their livers. These had characteristics similar to the green pigments produced in the livers of rats after the administration of 2-allyl-2-isopropylacetamide. No green pigments could be extracted from the livers of control rats or those given norethandrolone, estradiol or progesterone.