Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0600142 (hot flushes)
 1,242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microsomal cytochrome P450 (CYP 450) enzyme aromatase belongs to CYP 19 super family. It is involved in the conversion of androgens to estrogens. In postmenopausal women the main sites of aromatisation are skin, adipose tissue and breast. Aromatase localized in breast tumor produces sufficient estrogen for its proliferation. Hence it is an important target for the treatment of hormone dependent breast cancer in postmenopausal women. There are mainly two types of aromatase inhibitors, one is steroidal another is nonsteroidal type. The first and second generation aromatase inhibitors encounter the undesirable drug- drug interactions besides being not very specific and plagued with pharmacokinetic problems. Third generation aromatase inhibitors developed recently are more potent and specific with a greater capacity to annihilate circulating estrogen levels. These agents have satisfactory pharmacokinetic profiles and are devoid of major drug-drug interactions. Third generation aromatase inhibitors became drugs of choice for both first and second line treatment of advanced breast cancer. Aromatase inhibitors can also be used for neoadjuvant therapy of breast cancer in which they have achieved better therapeutic efficacy than tamoxifen. Early results of ATAC (Armidex Tamoxifen Alone or Combination) trial suggest that anastrozole is superior to tamoxifen in adjuvant setting for disease free survival, particularly in receptor positive patients, and in reducing the incidence of contralateral breast cancer. Therapeutic potential of aromatase inhibitors stretches beyond the postmenopausal breast cancer treatment as they also play a role in the treatment of estrogen dependent benign and malignant conditions such as gynaecomastia, prostate cancer, fibroadenomata and the induction of ovulation. By virtue of their ability to reduce estrogen levels they pose problems like demineralization of bone, hot flushes and anti-implantation effects.
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PMID:Aromatase inhibitors: a new paradigm in breast cancer treatment. 1557 17

Tamoxifen, an oestrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole.
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PMID:Tamoxifen and CYP 2D6 inhibitors: caution. 2175 53

During the menopausal transition and early postmenopause, participants in the Seattle Midlife Women's Health Study (SMWHS) experienced one of the three symptom severity clusters identified through latent class analysis: severe hot flashes with moderate sleep, mood, cognitive, and pain symptoms (high-severity hot flash); low-severity hot flashes with moderate levels of all other symptom groups (moderate severity); and low levels of all symptom groups (low severity). In an effort to determine whether gene polymorphisms were associated with these symptom severity classes, we tested associations between gene polymorphisms in the estrogen synthesis pathways (cytochrome P450 19 [CYP 19] and 17 beta hydroxysteroid dehydrogenase [ 17HSDB1]) and the three symptom severity clusters. SMWHS participants ( N = 137) recorded symptoms monthly in diaries and provided buccal smears for genotyping. Multilevel latent class analysis with multinomial regression was used to determine associations between gene polymorphisms and symptom severity clusters. Only the 17HSDB1 polymorphisms ( rs615942 and rs592389) were associated significantly with the high-severity hot flash cluster versus the low-severity symptom cluster. None of the polymorphisms was associated with the moderate-severity cluster versus the low-severity symptom cluster. Findings of associations of the 17HSDB1 polymorphisms with the high-severity hot flash symptom cluster are consistent with those of an association between 17HSDB1 polymorphisms and hot flashes in the Study of Women and Health Across the Nation population and our previous findings of associations between these polymorphisms with greater estrone levels.
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PMID:Polymorphisms in Estrogen Synthesis Genes and Symptom Clusters During the Menopausal Transition and Early Postmenopause: Observations From the Seattle Midlife Women's Health Study. 2933 60