Atamestane is not a metabolite of methenolone in human metabolism due to differences in their chemical structures, metabolic pathways, and the specific enzymatic processes involved in their breakdown. Below is a detailed explanation:
1. Chemical Structure Differences
• Atamestane: Atamestane (1-methylandrosta-1,4-diene-3,17-dione) has the molecular formula C20H26O2 and a molar weight of 298.4 g/mol. It is a steroidal aromatase inhibitor with a characteristic 1-methyl group and a 3,17-dione structure, featuring two ketone groups at positions 3 and 17, and double bonds at positions 1 and 4 in the steroid A-ring.
• Methenolone: Methenolone exists as Methenolone Acetate (C22H32O3, 344.49 g/mol) or Methenolone Enanthate (C27H42O3, 414.62 g/mol). It is a 17β-hydroxy-1-methyl-5α-androst-1-en-3-one, meaning it has a hydroxyl group at position 17 (in the acetate or enanthate ester form) and a single double bond at position 1, with a 3-keto group. The key structural differences include:
• Methenolone has a 17β-hydroxyl group (or esterified hydroxyl), whereas atamestane has a 17-keto group.
• Atamestane has an additional double bond at position 4 (making it a 1,4-diene), which methenolone lacks.
• The ester groups in methenolone (acetate or enanthate) are cleaved during metabolism, but the resulting core structure (methenolone base) is still distinct from atamestane.
These structural differences mean that transforming methenolone into atamestane would require specific enzymatic modifications (e.g., oxidation of the 17β-hydroxyl to a ketone and introduction of a double bond at position 4) that are not typically part of human metabolic pathways for anabolic steroids like methenolone.
2. Human Metabolic Pathways
• Methenolone Metabolism: In humans, methenolone (as acetate or enanthate) undergoes metabolism primarily through:
• Ester hydrolysis: The acetate or enanthate ester is cleaved by esterases, yielding the parent compound, methenolone (17β-hydroxy-1-methyl-5α-androst-1-en-3-one).
• Phase I metabolism: This involves reduction, oxidation, or hydroxylation, primarily at the 3-keto or 17β-hydroxy groups, and reduction of the 1,2-double bond. Common metabolites include 3α-hydroxy-1-methylen-5α-androstan-17-one and other hydroxylated derivatives, as identified in urinary excretion studies.
• Phase II metabolism: Conjugation with glucuronides or sulfates for excretion.
• The primary metabolites of methenolone retain the 1-methyl and 5α-reduced structure, with modifications mainly at the 3- or 17-positions. None of these transformations produce a 1,4-diene-3,17-dione structure like atamestane.
• Atamestane: Atamestane is a synthetic compound not naturally produced in the body or derived from other steroids in human metabolism. Its metabolism involves:
• Hydroxylation of the 1-methyl group.
• 5β-reduction and C-6 hydroxylation.
• Action of 17β-hydroxysteroid dehydrogenase, which can reduce the 17-keto group to a hydroxyl group in some metabolites. These pathways are distinct from those of methenolone, and there is no evidence that methenolone’s metabolic transformations in humans (e.g., via cytochrome P450 enzymes or steroid dehydrogenases) yield atamestane’s specific structure.
3. Fungal Biotransformation vs. Human Metabolism
• While atamestane has been identified as a metabolite (metabolite 12) of methenolone acetate in biotransformation studies using the fungus Fusarium lini, this is not relevant to human metabolism. Fungal biotransformation involves unique microbial enzymes that perform specific reactions, such as:
• Dehydrogenation to introduce a double bond at position 4.
• Oxidative cleavage of the acetate ester and oxidation of the 17β-hydroxyl to a 17-keto group
• These enzymatic capabilities are not present in human liver or other tissues. Human steroid metabolism primarily involves cytochrome P450 enzymes, reductases, and hydroxylases that do not catalyze the precise combination of reactions needed to convert methenolone’s 17β-hydroxy-1-methyl-5α-androst-1-en-3-one structure into atamestane’s 1-methylandrosta-1,4-diene-3,17-dione structure.
4. Enzymatic Feasibility
• To convert methenolone to atamestane in humans, the following would be required:
• Oxidation of the 17β-hydroxyl to a 17-keto group: This is possible via 17β-hydroxysteroid dehydrogenase, but it is not a dominant pathway for methenolone, which is more likely to undergo conjugation or reduction.
• Introduction of a double bond at position 4: This requires a specific dehydrogenase or desaturase enzyme, which is not typically involved in human metabolism of 5α-reduced steroids like methenolone. The 1,4-diene structure is characteristic of certain synthetic steroids (e.g., boldenone derivatives) but not a natural metabolite of methenolone.
• Retention of the 1-methyl group and 3-keto group: While these are preserved, the additional double bond and 17-keto formation are not consistent with methenolone’s known metabolic fate.
• Human enzymes involved in steroid metabolism (e.g., 3α/3β-hydroxysteroid dehydrogenases, 5α/5β-reductases, or cytochrome P450 enzymes) do not facilitate this specific transformation. In contrast, Fusarium lini possesses unique microbial enzymes capable of these reactions, which explains why atamestane can be produced in fungal biotransformation but not in humans.
5. Literature and Evidence
• Studies on methenolone metabolism in humans, such as those using gas chromatography-mass spectrometry (GC-MS) to detect urinary metabolites, identify compounds like 3α-hydroxy-1-methylen-5α-androstan-17-one and other hydroxylated or conjugated derivatives, but not atamestane.
• Atamestane is described as a synthetic compound designed as an aromatase inhibitor, not a naturally occurring metabolite of other steroids in human physiology.
• The fungal biotransformation study with Fusarium lini explicitly notes atamestane as a product of microbial metabolism, not human metabolism, reinforcing that this transformation is specific to the fungal enzymatic system.
Conclusion
Atamestane cannot be a metabolite of methenolone in human metabolism because the structural transformations required (17β-hydroxyl oxidation to a ketone and introduction of a 4,5-double bond) are not catalyzed by human enzymes involved in methenolone metabolism. The production of atamestane from methenolone acetate in Fusarium lini is due to unique microbial enzymes absent in humans. Thus, in the context of human pharmacokinetics, atamestane is not a metabolite of methenolone or its esters.
