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Effects of 1-α- acetylmethadol on neonatal androgen induced imprinting in the rat

University of British Columbia

It is well known that an age and sex dependent difference exists for the hepatic microsomal metabolism of certain compounds in the rat. With certain enzymes this difference has been shown to be dependent on the presence of testosterone in the male neonate giving rise to the term neonatal androgen induced imprinting. Removal of testosterone from the male neonate will result in the reduction or abolition of imprinting and of the expression of the sex difference at puberty. Since opiates are known to reduce plasma testosterone levels and have inhibitory effects on the prostate gland and seminal vesicle, we have postulated that in utero and neonatal exposure to opiates will inhibit imprinting as expressed by a decrease in the sex dependent hepatic microsomal enzyme activities. To test this hypothesis l-α-acetylmethadol-HCl (LAAM) was administered via the drinking water to female Wistar rats throughout pregnancy and lactation. The dose was increased throughout pregnancy such that an average maximum of 1.15 ± 0.10 mg/kg/d ay was achieved during the third trimester. Controls were pair fed and watered. Pups were not removed to surrogate dams as the neonatal period is likely to be important to imprinting. On day 21 pups were weaned from LAAM and control dams, and separated as to their sex and experimental groups. All pups received lab chow and water ad libitum until they reached maturity (days 90-120). The apparent Km, Vmax, and basal specific activities were determined for aminopyrine N-demethylase (AP), ethylmorphine N-demethylase (ET), aniline hydroxylase (AN), and benzo(a)pyrene hydroxylase (BP) from the hepatic microsomal fraction of the mature male and female offspring. Differences were considered significant at p < 0.05 using a two-tailed Student's t-test. The dose of LAAM administered did not produce any neonatal withdrawal or inhibition of development of the pups. In the adult male, in utero and neonatal exposure to LAAM resulted in decreases in Km for AP, Vmax for AN and basal specific activity for ET, and increases in the Km, Vmax and basal specific activity for BP. For the female LAAM produced an increase in Km for AP and a decrease in the Vmax for ET and BP as well as a decrease in the basal specific activity of BP. These results show that in utero and neonatal exposure to LAAM affects certain hepatic microsomal enzyme activities expressed in the mature rat. Furthermore, these observations are consistent with inhibitory effects of LAAM on imprinting resulting in a change in the profile of cytochromes P-45D present in the hepatic microsomal fraction.

Text

2010-03-18

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http://hdl.handle.net/2429/22100

Pharmaceutical Sciences

University of British Columbia

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