Relationship between CYP3A activity and breast cancer susceptibility in Chinese Han women.
BACKGROUND
Breast cancer is the most frequent type of tumor in women. The main cause of breast cancer remains unknown. Extensive studies have shown that endogenous steroid hormones, especially estrogens, are important in the development and the progression of breast cancer, and the carcinogenesis of estrogens is related to their major oxidative metabolites, 16alpha-hydroxyestrogens and 4-hydroxyestrogens. CYP3A plays a major role in the 4- and 16alpha-hydroxylation of estrogens. Furthermore, CYP3A is present in human mammary epithelial cells and expressed higher and more frequently in malignant breast cells than in the adjacent normal breast tissue. Hence, it will be significant to perform more work to determine the association between CYP3A activity and breast cancer susceptibility.


OBJECTIVE
To evaluate the relationship of CYP3A activity to breast cancer susceptibility in Chinese Han women using the plasma 1-hydroxymidazolam (1-OHMDZ) to midazolam (MDZ) ratio as the marker of CYP3A activity.


METHODS
One hundred and twenty-nine Chinese Han female breast tumor patients and 121 healthy unrelated female volunteers were enrolled in the current study. After an overnight fast, each subject was administered a single oral dose (7.5 mg) of midazolam. Blood samples (5 ml) were drawn at 1 h after the drug administration. The concentration of parent MDZ and its major metabolite 1-OH-MDZ was measured in all the plasma samples using high-performance liquid chromatography.


RESULTS
Complete chromatographic data on plasma ratios of 1-OHMDZ to MDZ for 103 cases of breast cancer and 114 controls were available. The plasma concentration ratios of 1-OHMDZ to MDZ were 0.4520+/-0.2318 and 0.3298+/-0.1610 for the malignant cases and the controls, respectively. A higher CYP3A activity was found in the breast cancer cases than in the controls ( P<0.001), and the CYP3A activity of patients with lymph-node metastasis was higher than that of patients without lymph-node metastasis ( P=0.028). CYP3A activity in estrogen receptor or progesterone receptor positive cases was the same as in estrogen receptor or progesterone receptor negative cases ( P=0.124, 0.175).


CONCLUSIONS
Our results indicate that high CYP3A activity may contribute to breast cancer disease genesis and may promote breast cancer to lymph-node metastasis.
Huang
Ping
P
Tumor Hospital of Hunan Province, Changsha, Hunan, People's Republic of China.
Zhu
Bing
B
Wang
Lian-Sheng
LS
Ouyang
Dong-Sheng
DS
Huang
Song-Lin
SL
Chen
Xiao-Ping
XP
Zhou
Hong-Hao
HH
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D044466:Asian People; D001943:Breast Neoplasms / Q000208:ethnology / Q000378:metabolism* / Q000473:pathology; D002681:China; D051544:Cytochrome P-450 CYP3A; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008874:Midazolam / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012307:Risk Factors
D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C040081:1-hydroxymethylmidazolam; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam