Molecular Dynamics Analysis Reveals Structural Insights into Mechanism of Nicotine N-Demethylation Catalyzed by Tobacco Cytochrome P450 Mono-Oxygenase

CYP82E4, a cytochrome P450 monooxygenase, has nicotine N-demethylase (NND) activity, which mediates the bioconversion of nicotine into nornicotine in senescing tobacco leaves. Nornicotine is a precursor of the carcinogen, tobacco-specific nitrosamine. CYP82E3 is an ortholog of CYP82E4 with 95% sequence identity, but it lacks NND activity. A recent site-directed mutagenesis study revealed that a single amino acid substitution, i.e., cysteine to tryptophan at the 330 position in the middle of protein, restores the NND activity of CYP82E3 entirely. However, the same amino acid change caused the loss of the NND activity of CYP82E4. To determine the mechanism of the functional turnover of the two molecules, four 3D structures, i.e., the two molecules and their corresponding cys–trp mutants were modeled. The resulting structures exhibited that the mutation site is far from the active site, which suggests that no direct interaction occurs between the two sites. Simulation studies in different biological scenarios revealed that the mutation introduces a conformation drift with the largest change at the F-G loop. The dynamics trajectories analysis using principal component analysis and covariance analysis suggests that the single amino acid change causes the opening and closing of the transfer channels of the substrates, products, and water by altering the motion of the F-G and B-C loops. The motion of helix I is also correlated with the motion of both the F-G loop and the B-C loop and; the single amino acid mutation resulted in the curvature of helix I. These results suggest that the single amino acid mutation outside the active site region may have indirectly mediated the flexibility of the F-G and B-C loops through helix I, causing a functional turnover of the P450 monooxygenase

Postpartum women’s use of medicines and breastfeeding practices: a systematic review

The objectives of this article are to systematically review i) the extent of medicine use in postpartum women, and ii) the impact of maternal medicine use (excluding contraceptives and galactogogues) on breastfeeding outcomes (initiation and/or duration). PubMed, Medline (Ovid), Scopus (Elsevier), Cinahl (EBSCO), PsycINFO (Ovid), Embase (Ovid) and Web of Science (ISI) databases were searched to find original studies on medicine use in women after the birth. Additional studies were identified by searching Google Scholar, Wiley Online Library, Springer Link, selected journals and from the reference list of retrieved articles. Observational studies with information about postpartum women’s use of any type of medicine either for chronic or acute illnesses with or without breastfeeding information were included. The majority of relevant studies suggest that more than 50 % of postpartum women (breastfeeding or not) required at least one medicine. Due to the lack of uniform medication use reporting system and differences in study designs, settings and samples, the proportion of medicine use by postpartum women varies widely, from 34 to 100 %. Regarding the impact of postpartum women’s medicine use on breastfeeding, a few studies suggest that women’s use of certain medicines (e.g. antiepileptics, propylthiouracil, antibiotics) during lactation can reduce initiation and/ or duration of breastfeeding. These studies are limited by small sample size, and with one exception, all were conducted in Canada more than a decade ago. Large scale studies are required to establish the relationship between maternal medicine use and breastfeeding, considering type of illness, period of use and total duration of medicine use

The use of herbal medicines during breastfeeding: A population-based survey in Western Australia

Background: Main concerns for lactating women about medications include the safety of their breastfed infants and the potential effects of medication on quantity and quality of breast milk. While medicine treatments include conventional and complementary medicines, most studies to date have focused on evaluating the safety aspect of conventional medicines. Despite increasing popularity of herbal medicines, there are currently limited data available on the pattern of use and safety of these medicines during breastfeeding. This study aimed to identify the pattern of use of herbal medicines during breastfeeding in Perth, Western Australia, and to identify aspects which require further clinical research. Methods: This study was conducted using a self-administered questionnaire validated through two pilot studies. Participants were 18 years or older, breastfeeding or had breastfed in the past 12 months. Participants were recruited from various community and health centres, and through advertising in newspapers. Simple descriptive statistics were used to summarise the demographic profile and attitudes of respondents, using the SPSS statistical software. Results: A total of 304 questionnaires from eligible participants were returned (27.2% response rate) and analysed. Amongst the respondents, 59.9% took at least one herb for medicinal purposes during breastfeeding, whilst 24.3% reported the use of at least one herb to increase breast milk supply. Most commonly used herbs were fenugreek (18.4%), ginger (11.8%), dong quai (7.9%), chamomile (7.2%), garlic (6.6%) and blessed thistle (5.9%). The majority of participants (70.1%) believed that there was a lack of information resources, whilst 43.4% perceived herbal medicines to be safer than conventional medicines. Only 28.6% of users notified their doctor of their decision to use herbal medicine (s) during breastfeeding; 71.6% had previously refused or avoided conventional medicine treatments due to concerns regarding safety of their breastfed infants. Conclusions: The use of herbal medicines is common amongst breastfeeding women, while information supporting their safety and efficacy is lacking. This study has demonstrated the need for further research into commonly used herbal medicines. Evidence-based information should be available to breastfeeding women who wish to consider use of all medicines, including complementary medicines, to avoid unnecessary cessation of breastfeeding or compromising of pharmacotherapy