Effects of methoxychlor and its metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane on human and rat 17?-hydroxylase/17,20-lyase activity.
Toxicol Lett. 2014 Jan 19;
Authors: Ye L, Chen X, Li X, Zhu Q, Yu L, Guo J, Chen B, Akingbemi BT, Ge RS, Li H
Abstract
Exposure to methoxychlor, an agricultural pesticide, has been associated with reduced testicular androgen secretion. However, methoxychlor is converted to 2,2-bis-(p-hydroxyphenyl)-1,1, 1-trichloroethane (HPTE) in the liver, which then acts as its biologically active metabolite. Both methoxychlor and HPTE have been credited with estrogenic properties and have a weak anti-androgenic activity. However, the exact mechanisms of steroidogenic enzyme inhibition remain to be clarified. In the present study, human and rat testis microsomes were employed to investigate the inhibitory activities of methoxychlor and HPTE on 17?-hydroxylase/17,20-lyase (CYP17A1). The CYP17A1 enzyme is critical for androgen biosynthesis and catalyzes conversion of progesterone into androstenedione. The results demonstrated that HPTE directly inhibited human and rat CYP17A1 activities, while methoxychlor had no effects on this enzyme activity even at a concentration of 100?M. The IC50 values of HPTE were 1.13±0.10 (human) and 6.87±0.13?M (rat), respectively. When HPTE was incubated with rat immature Leydig cells, it also inhibited CYP17A1 activity with an IC50 value of 6.29±0.1?M. Results of enzyme inhibition were supported by the observation that HPTE inhibited luteinizing hormone-stimulated 5?-androstane-3?, 17?-diol and testosterone secretion by immature Leydig cells with IC50 values of 6.61±0.03 and 3.78±0.003?M, respectively. The mode of action of HPTE on CYP17A1 activity was determined to be uncompetitive with the substrate progesterone. In conclusion, HPTE, the metabolite of MXC, directly inhibited human and rat testis CYP17A1 activities.
PMID: 24451217 [PubMed - as supplied by publisher]
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Toxicol Lett. 2014 Jan 19;
Authors: Ye L, Chen X, Li X, Zhu Q, Yu L, Guo J, Chen B, Akingbemi BT, Ge RS, Li H
Abstract
Exposure to methoxychlor, an agricultural pesticide, has been associated with reduced testicular androgen secretion. However, methoxychlor is converted to 2,2-bis-(p-hydroxyphenyl)-1,1, 1-trichloroethane (HPTE) in the liver, which then acts as its biologically active metabolite. Both methoxychlor and HPTE have been credited with estrogenic properties and have a weak anti-androgenic activity. However, the exact mechanisms of steroidogenic enzyme inhibition remain to be clarified. In the present study, human and rat testis microsomes were employed to investigate the inhibitory activities of methoxychlor and HPTE on 17?-hydroxylase/17,20-lyase (CYP17A1). The CYP17A1 enzyme is critical for androgen biosynthesis and catalyzes conversion of progesterone into androstenedione. The results demonstrated that HPTE directly inhibited human and rat CYP17A1 activities, while methoxychlor had no effects on this enzyme activity even at a concentration of 100?M. The IC50 values of HPTE were 1.13±0.10 (human) and 6.87±0.13?M (rat), respectively. When HPTE was incubated with rat immature Leydig cells, it also inhibited CYP17A1 activity with an IC50 value of 6.29±0.1?M. Results of enzyme inhibition were supported by the observation that HPTE inhibited luteinizing hormone-stimulated 5?-androstane-3?, 17?-diol and testosterone secretion by immature Leydig cells with IC50 values of 6.61±0.03 and 3.78±0.003?M, respectively. The mode of action of HPTE on CYP17A1 activity was determined to be uncompetitive with the substrate progesterone. In conclusion, HPTE, the metabolite of MXC, directly inhibited human and rat testis CYP17A1 activities.
PMID: 24451217 [PubMed - as supplied by publisher]
This is an automated post
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