| Summary: | 碩士 === 國立臺灣大學 === 毒理學研究所 === 91 === Three tremogenic mycotoxines, designated as territrem A, B and C (TRA, TRB and TRC) were isolated from a chloroform extract of rice culture of Aspergillus terreus 23-1.The metabolism of TRA in liver microsomes of adult male and female rats have been studied. Three metabolites of TRA were formed by three sequential oxidative steps in male rats. There are first, hydroxylation at the 4b-C methyl group of TRA to form MA1; second, oxidation at 4b-C hydroxyl group of MA1 to form MAX; and third, decarbonylation at the 4b-C oxo group of MAX to form MA2. However, in female only MA1 was formed from TRA. Further, studies of cytochrome P450 isforms catalyzing TRA metabolism revealed that MA1 formation is catalyzed by both CYP3A1 and CYP3A2, while the formation of MAX and MA2 are catalyzed by CYP3A2. The sex difference of both amounts of protein and mRNA of CYP3A1/2 expression and territrems metabolism were examined in the present study.
Many studies concerning age-related changes in CYP450 linked to metabolism of xenobiotics and drug have been reported. Therefore, next study of CYP3A1 and CYP3A2 related to age and sex hormone are our major concern.
In the present studies, the following results were obtained: (1)Both protein and mRNA of CYP3A1 are constitutively expressed in both gender at 2- to 76-week-old age. (2)The protein levels and mRNA of CYP3A2 constitutively expressed in 2- to 52-week-old male rats, but they decreased after 76-week-old age, and decreased in female rat when after 6-week-old. (3)The expression of CYP3A1 or CYP3A2 in male rats are generally higher than female rats. (4)Formation of the different metabolites was due to change of aromatic moiety of territrems. (5)Formation of MAX and MA2 decreased after 52-week-old male rats and ceased after 6-week-old female rats. (6)The amount of MB2 formed in female rats was less than in male rats, but the amount of MB1 (TRC metabolites) formed in female rats was higher than male rats. (7)The protein levels of CYP3A2, production of MAX and MA2 were restored by administration on high dose testosterone (750 mg) in the castrated male rats.
Therefore, it is concluded that: (1) The metabolism of TRA have sexual difference were related to the protein and mRNA expression of CYP3A2. The different metabolites formed could be due to the modification of the chemical structure of the aromatic moiety of territrems. The protein levels and mRNA expression of CYP3A2 and efficiency of territrems metabolism were decreased after 76-week-old that cause feminization at elder age of male rats. (2)Testosterone status modulated CYP3A2 expression and caused sex differenced of metabolism. For instances, serum level of testosterone decreased after aging and then changed territrems metabolism efficiency. In conclusion, age- and gender-related changes on territrems metabolism were due to CYP3A2 expression which regulated by testosterone.
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