Suppression of the constitutive, male-specific rat hepatic cytochrome P-450 2c and its mRNA by 3,4,5,3',4',5'-hexachlorobiphenyl and 3-methylcholanthrene.

Rat liver cytochrome P-450 2c (P-450 2c) is a constitutive, male-specific enzyme that oxidatively metabolizes both steroid hormones and liphophilic foreign compounds. Exposure of adult male rats to certain xenobiotics can lead to a decrease in the expression of hepatic P-450 2c. The present studies were undertaken to examine the mechanism of this decrease. Treatment of adult male rats with 3-methylcholanthrene (3-MC) or 3,4,5,3',4',5'-hexachlorobiphenyl (HCB) (two compounds known to induce P-450c and P-450d as a consequence of their interaction with the aromatic hydrocarbon receptor) decreased hepatic content of P-450 2c and its associated steroid hormone 2 alpha- and 16 alpha-hydroxylase activities. Moreover, the present studies demonstrate that decreases in hepatic content of P-450 2c mRNA (determined by electrophoretic analysis of immunoprecipitated translational products) fully account for the effects of 3-MC and HCB on P-450 2c. HCB (50 mg/kg) produced the most striking decrease in P-450 2c and its mRNA, virtually eliminating their expression in hepatic tissue. The time course and dose-response for the decrease in P-450 2c and its mRNA differed markedly from that for induction of P-450c, indicating that the effects of HCB on the two proteins may involve different mechanisms. Additional experiments demonstrated that the sex difference in hepatic expression of P-450 2c is the result of a greater than 5-fold higher content of P-450 2c mRNA in male as compared to female rats. HCB decreased serum testosterone levels by greater than 98% at 5 days in adult male rats. However, the decrease in P-450 2c and serum testosterone levels was not accompanied by an increase in serum estradiol levels or induction of the female-specific enzyme P-450 2d. The present findings clearly establish that the decrease in P-450 2c produced by administration of HCB and 3-MC is the result of a decrease in the hepatic content of P-450 2c mRNA. These xenobiotics may decrease transcription of the mRNA for P-450 2c as a consequence of binding to the aromatic hydrocarbon receptor, or, alternatively, may interfere with the hormonal regulation of the mRNA for this male-specific P-450 enzyme.

3-(Trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine photolabels a substrate-binding site of rat hepatic cytochrome P-450 form PB-4.

Hepatic microsomes isolated from untreated male rats or from rats pretreated with phenobarbital (PB) or 3-methylcholanthrene (3-MC) were labeled with the hydrophobic, photoactivated reagent 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine ([125I]TID). [125I]TID incorporation into 3-MC- and PB-induced liver microsomal protein was enhanced 5- and 8-fold, respectively, relative to the incorporation of [125I]TID into uninduced liver microsomes. The major hepatic microsomal cytochrome P-450 forms inducible by PB and 3-MC, respectively designated P-450s PB-4 and BNF-B, were shown to be the principal polypeptides labeled by [125I]TID in the correspondingly induced microsomes. Trypsin cleavage of [125I]TID-labeled microsomal P-450 PB-4 yielded several radiolabeled fragments, with a single labeled peptide of Mr approximately 4000 resistant to extensive proteolytic digestion. The following experiments suggested that TID binds to the substrate-binding site of P-450 PB-4. [125I]TID incorporation into microsomal P-450 PB-4 was inhibited in a dose-dependent manner by the P-450 PB-4 substrate benzphetamine. In the absence of photoactivation, TID inhibited competitively about 80% of the cytochrome P-450-dependent 7-ethoxycoumarin O-deethylation catalyzed by PB-induced microsomes with a Ki of 10 microM; TID was a markedly less effective inhibitor of the corresponding activity catalyzed by microsomes isolated from uninduced or beta-naphthoflavone-induced livers.(ABSTRACT TRUNCATED AT 250 WORDS)

Legal abortions among teenagers in Canada, 1974 through 1978.

Between August 1969, when the amendment to the Criminal Code went into effect, and December 1978 about 397 000 legal abortions were performed in hospitals with therapeutic abortion committees in Canada. During the 5-year period 1974-78 abortions in females under 20 years of age accounted for 30.9% of all the legal abortions performed in Canada on Canadian residents, and the abortion rate per 1000 women aged 15 to 19 years increased from 13.6 to 16.3. During 1974-77 the proportion of women in whom the gestation period was more than 12 weeks at the time of abortion was 25.3% for teenagers (females under 20 years of age) but only 14.6% for women aged 20 years or over. In 1976 the teenage abortion rate was lower in Canada (14.5) than in the United States (36.2%), Sweden (28.5), Hungary (26.4), Denmark (26.0), Norway (22.7), Finland (20.3), and England and Wales (15.4).

PIP: After the liberalization of Canadian abortion law in 1969, the incidence of abortion increased every year between 1970 and 1978. About 397,000 legal abortions were recorded in hospitals with therapeutic abortion committee in Canada. During the period 1974-78, abortions in females under 20 years of age comprised 30.9% of all legal abortions, and abortion rate per 1000 women aged 15 to 19 years increased from 13.6 to 16.3. Inspite of this, the overall abortion rates and rates for teenagers are lower in Canada than in most of the developed countries (U.S., 36.2; Sweden, 28.5; Hungary, 26.4; Denmark, 26.0; Norway, 22.7; Finland, 20.3; and Engalnd and Wales, 15.4). The differences were attributed to local abortion laws, population structure, social and economic conditions, personal attitudes and beliefs about abortion, and knowledge and practice of methods of birth control.