The effect of methadone and buprenorphine on human placental aromatase

Olga L. Zharikova; Sujal V. Deshmukh; Tatiana N. Nanovskaya; Gary D.V. Hankins; Mahmoud S. Ahmed

doi:10.1016/j.bcp.2005.12.035

The effect of methadone and buprenorphine on human placental aromatase

Olga L. Zharikova, Sujal V. Deshmukh, Tatiana N. Nanovskaya, Gary D.V. Hankins, Mahmoud S. Ahmed

Obstetrics & Gynecology

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Methadone and buprenorphine (BUP) are used for treatment of the pregnant opiate addict. CYP19/aromatase is the major placental enzyme responsible for the metabolism of methadone to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and BUP to norbuprenorphine (norBUP). The aim of this investigation was to determine the effects of methadone and BUP on the activity of placental microsomal aromatase in the conversion of its endogenous substrates testosterone to 17β-estradiol (E₂) and 16α-hydroxytestosterone (16-OHT) to estriol (E₃). The conversion of testosterone and 16-OHT by human placental microsomes exhibited saturation kinetics, and the apparent K_m values were 0.2 ± 1 and 6 ± 3 μM, respectively. V_max values for E₂ and E₃ formation were 70 ± 16 and 28 ± 10 pmol/mg protein min, respectively. Also, data obtained revealed that methadone and BUP are competitive inhibitors of testosterone conversion to E₂ and 16-OHT to E₃. The K _i for methadone inhibition of E₂ and E₃ formation were 393 ± 144 and 53 ± 28 μM, respectively, and for BUP the K_i was 36 ± 9 and 6 ± 1 μM. The higher potency of the two opiates and their metabolites in inhibiting E₃ formation is in agreement with the lower affinity of 16-OHT than testosterone to aromatase. Moreover, the metabolites EDDP and norBUP were weaker inhibitors of aromatase than their parent compounds. The determined inhibition constants of methadone and BUP for E₃ formation by a cDNA-expressed CYP19 preparation were similar to those for placental microsomes. Therefore, data reported here suggest that methadone, BUP, and their metabolites are inhibitors of androgen aromatization in the placental biosynthesis of estrogens.

Original language	English (US)
Pages (from-to)	1255-1264
Number of pages	10
Journal	Biochemical Pharmacology
Volume	71
Issue number	8
DOIs	https://doi.org/10.1016/j.bcp.2005.12.035
State	Published - Apr 14 2006

Keywords

Buprenorphine (BUP)
CYP19/aromatase
Estrogen formation
Human placenta
Methadone
Pregnant opiate addict

ASJC Scopus subject areas

Biochemistry
Pharmacology

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10.1016/j.bcp.2005.12.035

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title = "The effect of methadone and buprenorphine on human placental aromatase",

abstract = "Methadone and buprenorphine (BUP) are used for treatment of the pregnant opiate addict. CYP19/aromatase is the major placental enzyme responsible for the metabolism of methadone to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and BUP to norbuprenorphine (norBUP). The aim of this investigation was to determine the effects of methadone and BUP on the activity of placental microsomal aromatase in the conversion of its endogenous substrates testosterone to 17β-estradiol (E2) and 16α-hydroxytestosterone (16-OHT) to estriol (E3). The conversion of testosterone and 16-OHT by human placental microsomes exhibited saturation kinetics, and the apparent Km values were 0.2 ± 1 and 6 ± 3 μM, respectively. Vmax values for E2 and E3 formation were 70 ± 16 and 28 ± 10 pmol/mg protein min, respectively. Also, data obtained revealed that methadone and BUP are competitive inhibitors of testosterone conversion to E2 and 16-OHT to E3. The K i for methadone inhibition of E2 and E3 formation were 393 ± 144 and 53 ± 28 μM, respectively, and for BUP the Ki was 36 ± 9 and 6 ± 1 μM. The higher potency of the two opiates and their metabolites in inhibiting E3 formation is in agreement with the lower affinity of 16-OHT than testosterone to aromatase. Moreover, the metabolites EDDP and norBUP were weaker inhibitors of aromatase than their parent compounds. The determined inhibition constants of methadone and BUP for E3 formation by a cDNA-expressed CYP19 preparation were similar to those for placental microsomes. Therefore, data reported here suggest that methadone, BUP, and their metabolites are inhibitors of androgen aromatization in the placental biosynthesis of estrogens.",

keywords = "Buprenorphine (BUP), CYP19/aromatase, Estrogen formation, Human placenta, Methadone, Pregnant opiate addict",

author = "Zharikova, {Olga L.} and Deshmukh, {Sujal V.} and Nanovskaya, {Tatiana N.} and Hankins, {Gary D.V.} and Ahmed, {Mahmoud S.}",

note = "Funding Information: The authors appreciate the support of the National Institute on Drug Abuse drug supply program for providing methadone, EDDP, BUP, and norBUP. The authors appreciate the assistance of the medical staff, the Chairman's Research Group, and the Publication, Grant, and Media Support area of the Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas. This work was supported by a grant from the National Institute on Drug Abuse to Mahmoud S. Ahmed (DA-13431). ",

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AU - Zharikova, Olga L.

AU - Deshmukh, Sujal V.

AU - Nanovskaya, Tatiana N.

AU - Hankins, Gary D.V.

AU - Ahmed, Mahmoud S.

N1 - Funding Information: The authors appreciate the support of the National Institute on Drug Abuse drug supply program for providing methadone, EDDP, BUP, and norBUP. The authors appreciate the assistance of the medical staff, the Chairman's Research Group, and the Publication, Grant, and Media Support area of the Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas. This work was supported by a grant from the National Institute on Drug Abuse to Mahmoud S. Ahmed (DA-13431).

PY - 2006/4/14

Y1 - 2006/4/14

N2 - Methadone and buprenorphine (BUP) are used for treatment of the pregnant opiate addict. CYP19/aromatase is the major placental enzyme responsible for the metabolism of methadone to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and BUP to norbuprenorphine (norBUP). The aim of this investigation was to determine the effects of methadone and BUP on the activity of placental microsomal aromatase in the conversion of its endogenous substrates testosterone to 17β-estradiol (E2) and 16α-hydroxytestosterone (16-OHT) to estriol (E3). The conversion of testosterone and 16-OHT by human placental microsomes exhibited saturation kinetics, and the apparent Km values were 0.2 ± 1 and 6 ± 3 μM, respectively. Vmax values for E2 and E3 formation were 70 ± 16 and 28 ± 10 pmol/mg protein min, respectively. Also, data obtained revealed that methadone and BUP are competitive inhibitors of testosterone conversion to E2 and 16-OHT to E3. The K i for methadone inhibition of E2 and E3 formation were 393 ± 144 and 53 ± 28 μM, respectively, and for BUP the Ki was 36 ± 9 and 6 ± 1 μM. The higher potency of the two opiates and their metabolites in inhibiting E3 formation is in agreement with the lower affinity of 16-OHT than testosterone to aromatase. Moreover, the metabolites EDDP and norBUP were weaker inhibitors of aromatase than their parent compounds. The determined inhibition constants of methadone and BUP for E3 formation by a cDNA-expressed CYP19 preparation were similar to those for placental microsomes. Therefore, data reported here suggest that methadone, BUP, and their metabolites are inhibitors of androgen aromatization in the placental biosynthesis of estrogens.

AB - Methadone and buprenorphine (BUP) are used for treatment of the pregnant opiate addict. CYP19/aromatase is the major placental enzyme responsible for the metabolism of methadone to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and BUP to norbuprenorphine (norBUP). The aim of this investigation was to determine the effects of methadone and BUP on the activity of placental microsomal aromatase in the conversion of its endogenous substrates testosterone to 17β-estradiol (E2) and 16α-hydroxytestosterone (16-OHT) to estriol (E3). The conversion of testosterone and 16-OHT by human placental microsomes exhibited saturation kinetics, and the apparent Km values were 0.2 ± 1 and 6 ± 3 μM, respectively. Vmax values for E2 and E3 formation were 70 ± 16 and 28 ± 10 pmol/mg protein min, respectively. Also, data obtained revealed that methadone and BUP are competitive inhibitors of testosterone conversion to E2 and 16-OHT to E3. The K i for methadone inhibition of E2 and E3 formation were 393 ± 144 and 53 ± 28 μM, respectively, and for BUP the Ki was 36 ± 9 and 6 ± 1 μM. The higher potency of the two opiates and their metabolites in inhibiting E3 formation is in agreement with the lower affinity of 16-OHT than testosterone to aromatase. Moreover, the metabolites EDDP and norBUP were weaker inhibitors of aromatase than their parent compounds. The determined inhibition constants of methadone and BUP for E3 formation by a cDNA-expressed CYP19 preparation were similar to those for placental microsomes. Therefore, data reported here suggest that methadone, BUP, and their metabolites are inhibitors of androgen aromatization in the placental biosynthesis of estrogens.

KW - Buprenorphine (BUP)

KW - CYP19/aromatase

KW - Estrogen formation

KW - Human placenta

KW - Methadone

KW - Pregnant opiate addict

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The effect of methadone and buprenorphine on human placental aromatase

Abstract

Keywords

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