Biotransformation of zeranol: disposition and metabolism in the female rat, rabbit, dog, monkey and man

Migdalof, Bruce H.; Dugger, Harry A.; Heider, John G.; Coombs, R A; Terry, Martin

doi:10.3109/00498258309052257

Cited by 59 publications

(59 citation statements)

References 7 publications

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“…Although the methodology was aimed to be of qualitative nature only, a rough estimation of the conversion efficiency outlined only a low percentage of C‐C double bond‐reduced metabolites under the chosen in vitro conditions. These findings are in agreement with observations of earlier in vivo and in vitro studies conducted with different species and are also in line with the analysis of the administration study urine specimen depicted in Figure d, where zeranol, taleranol, and zearalanone were detected almost exclusively.…”

Section: Resultssupporting

confidence: 93%

Zeranol: doping offence or mycotoxin? A case‐related study

Thevis

Fußhöller

Schänzer

2011

Drug Testing and Analysis

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Zeranol ((7R,11S)-7,15,17-trihydroxy-11-methyl-12-oxabicyclo[12.4.0]octadeca-1(14),15,17-trien-13-one, also referred to as 7α-zearalanol, Ralone®, Frideron®, Ralgro®, etc.) is a semi-synthetic estrogenic veterinary drug with growth-promoting properties. Its use regarding animal husbandry has been prohibited in the European Union since 1981 and, due to its anabolic effects, it is further recognized as a banned substance in sport. Numerous studies were conducted concerning the identification of the illicit application of zeranol to domestic livestock. These studies also considered the natural occurrence of zeranol as a metabolite of the mycotoxin zearalenone and the issue of differentiating both scenarios, i.e. illegal use or unintended contamination. Human sports drug testing authorities are facing comparable challenges since the deliberate misuse of the (for human application non-approved) drug should be discriminated from adverse analytical findings resulting from the biotransformation of the mycotoxin zearalenone possibly ingested with contaminated food. The active drug (zeranol), its major human metabolites (zearalanone, 7β-zearalanol) and the mycotoxin (zearalenone) plus its major and unique metabolic products (α-zearalenol, β-zearalenol) have been monitored in routine doping controls by means of validated gas chromatography-(tandem) mass spectrometry (GC-(MS/)MS) methods since 1996, and between 2005 and 2010 four samples providing suspicious signals were detected. In agreement with literature data, in vitro metabolism studies demonstrated the metabolic pathway from zearalenone towards zeranol (and common metabolites). In contrast, an administration study urine sample (collected after oral application of 20 mg of zeranol) yielded only ultra-trace amounts of zearalenone and its characteristic metabolites, which supported the assumption that a mycotoxin contamination caused the finding of zeranol in the doping control specimens rather than a misuse of the anabolic agent.

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Section: Resultssupporting

confidence: 93%

Zeranol: doping offence or mycotoxin? A case‐related study

Thevis

Fußhöller

Schänzer

2011

Drug Testing and Analysis

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“…Due to its legal application as a growth-promoter in certain non-EU countries, the metabolic fate of Zeranol (a-ZAL) has been investigated in several species, including rats, humans, pigs, dogs, cattle, and rabbits (Migdalof et al, 1983;Bories and Suarez, 1989;Bories et al, 1991;Kleinova et al, 2002). In all species, the main hepatic phase I biotransformations consist in the oxidation of the C7-secondary alcoholic group to the corresponding -CO derivative, referred to as ZAN, as well as in the generation of the diastereoisomer b-ZAL, also known as taleranol, resulting from the aldo-ketoreductase-mediated reduction of the same alcoholic group.…”

Section: Modified Formsmentioning

confidence: 99%

Risks for animal health related to the presence of zearalenone and its modified forms in feed

Knutsen¹,

Alexander²,

Barregård³

et al. 2017

EFS2

147

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Zearalenone (ZEN), a mycotoxin primarily produced by Fusarium fungi, occurs predominantly in cereal grains. The European Commission asked EFSA for a scientific opinion on the risk to animal health related to ZEN and its modified forms in feed. Modified forms of ZEN occurring in feed include phase I metabolites a-zearalenol (a-ZEL), b-zearalenol (b-ZEL), a-zearalanol (a-ZAL), b-zearalanol (b-ZAL), zearalanone (ZAN) and phase II conjugates. ZEN has oestrogenic activity and the oestrogenic activity of the modified forms of ZEN differs considerably. For ZEN, the EFSA Panel on Contaminants in the Food Chain (CONTAM) established no observed adverse effect levels (NOAELs) for pig (piglets and gilts), poultry (chicken and fattening turkeys), sheep and fish (extrapolated from carp) and lowest observed effect level (LOAEL) for dogs. No reference points could be established for cattle, ducks, goats, horses, rabbits, mink and cats. For modified forms, no reference points could be established for any animal species and relative potency factors previously established from rodents by the CONTAM Panel in 2016 were used. The dietary exposure was estimated on 17,706 analytical results with high proportions of left-censored data (ZEN about 60%, ZAN about 70%, others close to 100%). Samples for ZEN were collected between 2001 and 2015 in 25 different European countries, whereas samples for the modified forms were collected mostly between 2013 and 2015 from three Member States. Based on exposure estimates, the risk of adverse health effects of feed containing ZEN was considered extremely low for poultry and low for sheep, dog, pig and fish. The same conclusions also apply to the sum of ZEN and its modified forms.

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“…A taxa desses metabólitos varia de acordo com a espécie. Em coelhos, o taleranol é o metabólito do zeranol (ERASMUSON et al, 1994;MIGDALOF et al, 1983).…”

Section: Resíduos De Agentes Anabólicosunclassified