On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production

Satoh, Takashi; Itoh, Shinji; Seki, Toshio; Itoh, Shungo; Nomura, Norikazu; Yoshizawa, Itsuo

doi:10.1016/s0960-0760(02)00154-1

Cited by 15 publications

(16 citation statements)

References 33 publications

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“…On the parenthesis of Fig. 4, in addition, the frequencies of gynecomastia associated with each drug as described in the package inserts 4) are shown, a well-defined correlation is not observed between these drugs and the frequencies.…”

Section: Discussionmentioning

confidence: 95%

“…As a result of studies on these possibilities, it was found that drugs that induce gynecomastia may also inhibit the 17b-HSD system as well as the phase I reaction of E2. 3,4) The above results indicate that the phase II reaction (conjugation) must also be taken into consideration as one of the reaction systems affecting the estrogen pool (Fig. 1).…”

mentioning

confidence: 87%

“…Estradiol 17-sulfate (E2-17S) was synthesized in our laboratory according to the method of Kirdani. 12) UDP-glucuronic acid (UDPGA) was obtained from Sigma Corp. (St. Louis, MA, U.S.A.). The same lots as those of a previous study were used for the 29 drugs 4) and for human hepatic microsomes (pooled) from ten male subjects.…”

Section: Reagentsmentioning

confidence: 99%

“…By confirming drug inhibition in those systems, we intend to develop a model unit reaction system for the determination of the percentage inhibition under identical conditions, and to determine its potential for clinical application. [2][3][4] The results obtained are discussed below.…”

mentioning

confidence: 98%

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Studies on the Interactions between Drugs and Estrogen. III. Inhibitory Effects of 29 Drugs Reported to Induce Gynecomastia on the Glucuronidation of Estradiol

Satoh¹,

Tomikawa

Takanashi

et al. 2004

Biological & Pharmaceutical Bulletin

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Although the drug-induced side effect of gynecomastia is, in many cases, considered to be a result of drug-estrogen interaction mediated by cytochrome P450 (CYP), the prediction of this side effect for inclusion in package inserts is difficult. This is because in addition to the phase I reaction, the effects of the drug on the entire enzyme system involved in the estrogen pool must be taken into consideration.Thus far, we have attempted to construct a system for predicting drug-induced gynecomastia by not only focusing on the phase I reaction, but also extending the sites of interaction to include estrogen production and regeneration systems. By confirming drug inhibition in those systems, we intend to develop a model unit reaction system for the determination of the percentage inhibition under identical conditions, and to determine its potential for clinical application.2-4) The results obtained are discussed below.The main route of metabolism of estradiol (E2) in humans is the phase I reaction of 2-hydroxylation, and although there are a lot of human hepatic CYP molecules that catalyze this reaction, their individual contribution ratios are unknown. The previous studies have shown that CYP3A4 has the highest contribution ratio at roughly 71%, 2) based on which a model unit reaction system using as reagent the recombinant CYP3A4 of an Escherichia coli expression system has been established. Next, the inhibitory effects of 29 drugs reported to induce gynecomastia on the 2-hydroxylation of E2 were investigated. Thirteen drugs of them showed high inhibition on the 2-hydroxylation, 3) but the rest 16 showed slight or no inhibition. Thus, gynecomastia by these drugs could not be explained in terms of the inhibition of the 2-hydroxylation alone.The possible candidates for the inhibition mechanism include drug inhibition of the estrogen production system involved in the estrogen pool (aromatase pathway), the estrogen regeneration system (sulfatase pathway), and/or 17b-hydroxysteroid dehydrogenase (17b-HSD) and its related systems. As a result of studies on these possibilities, it was found that drugs that induce gynecomastia may also inhibit the 17b-HSD system as well as the phase I reaction of E2. 3,4)The above results indicate that the phase II reaction (conjugation) must also be taken into consideration as one of the reaction systems affecting the estrogen pool (Fig. 1). The phase II reaction of E2 in humans consists primarily of the 3-or 17-glucuronidation by UDP-glucuronosyltransferase (UGT). UGT is divided into two subfamilies, UGT1 and UGT2, and each subfamily has some isoforms.5) UGT1A1 and UGT2B7 catalyze the 3-and 17-glucuronidation of E2, respectively, yielding estradiol 3-glucuronide (E2-3G) and estradiol 17-glucuronide (E2-17G).6) Because the two UGTs have low substrate specificity and are involved in the glucuronidation of drugs and other xenobiotic substances, [7][8][9][10][11] the interactions between E2 and drugs are predicted.This study was conducted for the purpose of investigating the inhibitory ef...

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Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 87%

Section: Reagentsmentioning

confidence: 99%

mentioning

confidence: 98%

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Studies on the Interactions between Drugs and Estrogen. III. Inhibitory Effects of 29 Drugs Reported to Induce Gynecomastia on the Glucuronidation of Estradiol

Satoh¹,

Tomikawa

Takanashi

et al. 2004

Biological & Pharmaceutical Bulletin

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“…Our patient was also treated with lansoprazole, which has also been reported to be a cause of gynecomastia. 7 Although lansoprazole was administered throughout the treatment period, the gynecomastia improved after discontinuation of MTX, so we consider that lansoprazole was not responsible for the gynecomastia in this case.…”

Section: Mtxmentioning

confidence: 72%

Gynecomastia associated with low-dose methotrexate therapy for rheumatoid arthritis

et al. 2007

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A 68-year-old man with a 3-year history of rheumatoid arthritis (RA) developed gynecomastia 3 months after beginning oral low-dose methotrexate (MTX) therapy. Four months after MTX therapy was discontinued, the gynecomastia symptoms improved. Only eight cases of gynecomastia resulting from low-dose MTX administration have been reported worldwide, and no cases have previously been reported in Japan. Although it occurs infrequently, gynecomastia resulting from low-dose MTX therapy should be considered in male patients with RA.

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Anti-androgenic Therapy Using Oral Spironolactone for Acne Vulgaris in Asians

et al. 2006

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On the inhibitory action of 29 drugs having side effect gynecomastia on estrogen production

Cited by 15 publications

References 33 publications

Studies on the Interactions between Drugs and Estrogen. III. Inhibitory Effects of 29 Drugs Reported to Induce Gynecomastia on the Glucuronidation of Estradiol

Studies on the Interactions between Drugs and Estrogen. III. Inhibitory Effects of 29 Drugs Reported to Induce Gynecomastia on the Glucuronidation of Estradiol

Gynecomastia associated with low-dose methotrexate therapy for rheumatoid arthritis

Anti-androgenic Therapy Using Oral Spironolactone for Acne Vulgaris in Asians

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