Rabbit Anti-Human CYP3A4 (a.a. 154-503) Polyclonal antibody

Context: Inter-individual differences in cortisol production and metabolism emerge with age and may be explained by genetic factors. Objective: To estimate the relative contributions of genetic and environmental factors to inter-individual differences in cortisol production and metabolism throughout adolescence. Design: Prospective follow-up study of twins. Setting: Nationwide register. Participants: 218 mono- and dizygotic twins (N = 109 pairs) born between 1995 amd 1996, recruited from the Netherlands Twin Register. Cortisol metabolites were determined in 213, 169, and 160 urine samples at the ages of 9, 12, and 17, respectively. Main outcome measures: The total contribution of genetic factors (broad-sense heritability) and shared and unshared environmental influences to inter-individual differences in cortisol production and activities of 5 alpha-reductase, 5 beta-reductase, and 11 beta-hydroxysteroid dehydrogenases and cytochrome P450 3A4. Results: For cortisol production rate at the ages of 9, 12, and 17, broad-sense heritability was estimated as 42%, 30%, and 0%, respectively, and the remainder of the variance was explained by unshared environmental factors. For cortisol metabolism indices, the following heritability was observed: for the A-ring reductases (5 alpha- and 5 beta-reductases), broad-sense heritability increased with age (to >50%), while for the other indices (renal 11 beta-HSD2, global 11 beta-HSD, and CYP3A4), the contribution of genetic factors was highest (68%, 18%, and 67%, respectively) at age 12. Conclusions: The contribution of genetic factors to inter-individual differences in cortisol production decreased between 12 and 17y, indicative of a predominant role of individual circumstances. For cortisol metabolism, distinct patterns of genetic and environmental influences were observed, with heritability that either increased with age or peaked at age 12y.

Prior exposures to chemicals/agents may alter epigenome in such a way that subsequent exposure to the same or different xenobiotic would produce different responses. Understanding the mechanism for this "priming" effect is of clinical significance in avoiding adverse drug-drug interactions. Here we reported a dramatic priming effect of dimethyl sulfoxide (DMSO) on pregnane X receptor (PXR)-mediated gene regulations and analyzed the underpinning epigenetic mechanism. We showed that DMSO (1.25-2.5 %) pretreatment has a profound effect in enhancing the expression of PXR target genes. This priming effect persisted up to 48 h. Mechanistically, DMSO pretreatment reduced H4K12 acetylation and therefore enhanced the subsequent rifampicin stimulated histone H4R3 methylation on the regulatory region of PXR target gene CYP3A4. We showed that protein arginine methyltransferase 1 (PRMT1), which methylates H4R3, was important for priming by DMSO. Inhibition of methyltransferase by the pharmacological inhibitor adenosine dialehyde (AdoX), or RNAi knockdown of PRMT1, abolished the DMSO priming effects. On the other hand, Trichostation A (TSA) pretreatment, which increases histone acetylation and therefore suppresses H4R3 methylation, also abolished the DMSO priming effects. Based on the above observation, we proposed a model of sequential order of histone methylation and acetylation on the transcription "relay".