TY - JOUR
T1 - The effect of opiates on the activity of human placental aromatase/CYP19
AU - Zharikova, Olga L.
AU - Deshmukh, Sujal V.
AU - Kumar, Meena
AU - Vargas, Ricardo
AU - Nanovskaya, Tatiana N.
AU - Hankins, Gary D.V.
AU - Ahmed, Mahmoud S.
N1 - Funding Information:
The project described was supported by grant number DA13431 from NIDA to M.S. Ahmed. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIDA. The authors appreciate the assistance of the medical staff, the Perinatal Research Group, and the Publication, Grant & Media Support area of the Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas.
PY - 2007/1/15
Y1 - 2007/1/15
N2 - Aromatase, cytochrome P450 19, is a key enzyme in the biosynthesis of estrogens by the human placenta. It is also the major placental enzyme that metabolizes the opiates l-acetylmethadol (LAAM), methadone, and buprenorphine (BUP). Methadone and BUP are used in treatment of the opiate addict and are competitive inhibitors of testosterone conversion to estradiol (E2) and 16α-hydroxytestosterone (16-OHT) to estriol (E3) by aromatase. The aim of this investigation is to determine the effect of 20 opiates, which can be administered to pregnant patients for therapeutic indications or abused, on E2 and E3 formation by placental aromatase. Data obtained indicated that the opiates increased, inhibited, or had no effect on aromatase activity. Their effect on E3 formation was more pronounced than that on E2 due to the lower affinity of 16-OHT than testosterone to aromatase. The Ki values for the opiates that inhibited E3 formation were sufentanil, 7 ± 1 μM; LAAM, 13 ± 8 μM; fentanyl, 25 ± 5 μM; oxycodone, 92 ± 22 μM; codeine, 218 ± 69 μM; (+)-pentazocine, 225 ± 73 μM. The agonists morphine, heroin, hydromorphone, oxymorphone, hydrocodone, propoxyphene, meperidine, levorphanol, dextrorphan, and (-)-pentazocine and the antagonists naloxone and naltrexone caused an increase in E3 formation by 124-160% of control but had no effect on E2 formation. Moreover, oxycodone and codeine did not inhibit E2 formation and the IC50 values for fentanyl, sufentanil, and (+)-pentazocine were >1000 μM. It is unlikely that the acute administration of the opiates that inhibit estrogen formation would affect maternal and/or neonatal outcome. However, the effects of abusing any of them during the entire pregnancy are unclear at this time.
AB - Aromatase, cytochrome P450 19, is a key enzyme in the biosynthesis of estrogens by the human placenta. It is also the major placental enzyme that metabolizes the opiates l-acetylmethadol (LAAM), methadone, and buprenorphine (BUP). Methadone and BUP are used in treatment of the opiate addict and are competitive inhibitors of testosterone conversion to estradiol (E2) and 16α-hydroxytestosterone (16-OHT) to estriol (E3) by aromatase. The aim of this investigation is to determine the effect of 20 opiates, which can be administered to pregnant patients for therapeutic indications or abused, on E2 and E3 formation by placental aromatase. Data obtained indicated that the opiates increased, inhibited, or had no effect on aromatase activity. Their effect on E3 formation was more pronounced than that on E2 due to the lower affinity of 16-OHT than testosterone to aromatase. The Ki values for the opiates that inhibited E3 formation were sufentanil, 7 ± 1 μM; LAAM, 13 ± 8 μM; fentanyl, 25 ± 5 μM; oxycodone, 92 ± 22 μM; codeine, 218 ± 69 μM; (+)-pentazocine, 225 ± 73 μM. The agonists morphine, heroin, hydromorphone, oxymorphone, hydrocodone, propoxyphene, meperidine, levorphanol, dextrorphan, and (-)-pentazocine and the antagonists naloxone and naltrexone caused an increase in E3 formation by 124-160% of control but had no effect on E2 formation. Moreover, oxycodone and codeine did not inhibit E2 formation and the IC50 values for fentanyl, sufentanil, and (+)-pentazocine were >1000 μM. It is unlikely that the acute administration of the opiates that inhibit estrogen formation would affect maternal and/or neonatal outcome. However, the effects of abusing any of them during the entire pregnancy are unclear at this time.
KW - Aromatase/CYP19
KW - Estrogen formation
KW - Human placenta
KW - Opiates
KW - Pregnancy
UR - http://www.scopus.com/inward/record.url?scp=33845201044&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845201044&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2006.08.019
DO - 10.1016/j.bcp.2006.08.019
M3 - Article
C2 - 17118343
AN - SCOPUS:33845201044
SN - 0006-2952
VL - 73
SP - 279
EP - 286
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 2
ER -