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DMD Highlight: Methadone is an Inactivating Substrate for Aromatase

Posted on 1/1/0001 12:00:00 AM | Tags:

Aromatase is a steroid-metabolizing enzyme, once thought to only catalyze the conversion of androgens to estradiol and estrone. However, results reported by Lu et al in the August, 2010, issue of Drug Metabolism and Disposition demonstrate that aromatase may also play a role in metabolizing methadone. In addition, the metabolism of methadone by aromatase results in destruction of the enzyme’s activity. It follows that the use of methadone may cause changes in endogenous steroid metabolism, as well as resulting in unanticipated drug-drug interactions. This work is the first known connection between methadone and steroid metabolism, suggesting the possibility that that inhibition of aromatase may contribute to the “endocrine” side effects experienced by patients taking methadone. See article at Drug Metab. Dispos. 2010, 38:1308-1313

Comments (1)

This is an interesting observation but some of the data don't seem to fit or are incomplete. If methadone were a mechanism-based inhibitor of aromatase, then one would expect to also see some component of competitive as well as time-dependent inhibition. This is not the case, as is apparent in Figure 4A. Furthermore, a control incubation with methadone but without NADPH was not reported, which would further confirm mechanism-based inactivation if no inactivation took place in the absence of NADPH. Also, it would have been interesting to have carried out the incubations in the presence of a thiol such as GSH to see if a reactive species could be trapped or not. This would give information as to whether the reactive intermediate actually leaves the enzyme active site or not before inactivation. Dialysis of the inactivated enyzme to try to remove the inhibitor was also not reported. Thus, I don't think there is enough evidence to conclude that the inhibition is mechanism-based. by Patrick Bednarski on 08/19/2010

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