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Steroid Δ4-Reductases: their Physiological Role and Significance
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
Several situations exist where the extent of cortisol being metabolized to tetrahydro metabolites is decreased with a corresponding increase in production of other metabolites such as 6β-hydroxycortisol, which is more polar and can be excreted in a free or unconjugated state. Examples of such situations include pregnancy,25 neonatal life,26 Cushing’s syndrome,27 and during the administration of drugs such as diphenylhydantoin and “o,p’-DDD” (2,2-bis (2-chlorophenyl-4-chlorophenyl)-1,1-dichloroethane).28,29
Identification of rhythmic human CYPs and their circadian regulators using synchronized hepatoma cells
Published in Xenobiotica, 2020
Min Chen, Cui Zhou, Tianpeng Zhang, Baojian Wu
Identification of CYP3A4 as a circadian gene whose expression oscillates with the times of the day helps to explain the observations that the pharmacokinetic behaviors of several drugs (e.g., triazolam and tacrolimus), primarily metabolized by the CYP3A4, vary significantly according to the dosing time (Min et al., 1997; Smith et al., 1986). Thus, identifying circadian genes among drug-metabolizing genes and elucidating the circadian regulation mechanisms are essential to advance chronopharmacokinetics and chronotherapeutics. Rhythmic expression of CYP3A4 is driven by the D-box binding proteins DBP and E4BP4 in a previous study (Takiguchi et al., 2007). Complementing this mechanism, we provided a new mechanism for diurnal expression of CYP3A4, namely, the E-box-driven mechanism (Figure 6). BMAL1 trans-activates CYP3A4 by directly acting on the E-box element in gene promoter (Figure 6). It was therefore proposed that rhythmic expression of CYP3A4 is generated and regulated via both E-box and D-box elements. CYP3A4 is capable of metabolizing not only pharmaceuticals (e.g., alfentanil, methadone and digitoxin) but also endogenous steroids such as cortisol, 17α-estradiol, testosterone, and progesterone (Torimoto et al., 2003; Zuber et al., 2002). In fact, the ratio of urinary 6β-hydroxycortisol to cortisol exhibits significant daily variation with a period of 24 h (Ohno et al., 2000). Since CYP3A4 is a major contributor to the metabolic conversion of cortisol to 6β-hydroxycortisol, our findings may help to explain circadian events of endobiotic metabolism in humans.
Cytochrome P450: genotype to phenotype
Published in Xenobiotica, 2020
Ideally, patients would be phenotyped before undergoing treatment and “cocktails” of drugs have been suggested which could identify PM or UM patients (Donzelli et al., 2014). This approach, however, relies on the metabolic pathways of the chosen drug being well-understood and does not necessarily allow for the (also polymorphic) metabolism by Phase 2 enzymes (Wendt et al., 2018). It has been suggested that measurement of metabolism of some endogenous compound might be useful if it utilised the same P450 isozyme as the drug of choice. Determination of the cortisol/6β-hydroxycortisol ratio has been used for CYP3A phenotyping but, as for most endogenous compounds, this is subject to circadian rhythms so that 24-hour collection of urine may be required with further analysis by GLC, HPLC or HPLC-MS. This tends to be complex to administer and expensive. Global metabonomic approaches have been suggested but these are currently non-validated and also expensive. Many investigators have therefore used genotyping (relatively simple and cheap, with rapid throughput) in attempts to identify those patients with metabolic capacities at either end of the range who may be most at risk of ADRs. Since the genome is constant (apart from epigenetic modifications) throughout a lifetime, this might in theory be a useful surrogate marker for toxicity. However, several factors combine to make this approach unreliable (Gallion et al., 2017; Karki et al., 2015; McGraw et al., 2018; Monte et al., 2012).
Impact of CYP2C19 genotype on voriconazole exposure and effect of voriconazole on the activity of CYP3A in patients with haematological malignancies
Published in Xenobiotica, 2021
Feng-Ru Huang, Chen Zhou, Xiao-Yan Zhang, Ye Shen, Hong-Wen Zhang, Yong-Qing Wang, Lu-Ning Sun
The ratio of 6β-hydroxycortisol to cortisol in plasma was used as an endogenous marker for in vivo CYP3A activity. VRC and metabolite levels were compared (according to sex and concomitant medication) using an independent-samples t-test. The influence of each genotype on VRC exposure and CYP3A activity was analysed by analysis of variance (ANOVA) and an independent-samples t-test. SPSS statistics 22.0 (IBM, Chicago, IL, USA) was used for data analysis, and differences with a P value less than 0.05 were considered significant.