Introduction to Human Cytochrome P450 Superfamily
Shufeng Zhou in Cytochrome P450 2D6, 2018
CYP27A1 (also called sterol 27-hydroxylase) is mainly expressed in the liver and located in mitochondria. CYP27A1 mRNA is also observed in macrophages (Gottfried et al. 2006), leukocytes (Shiga et al. 1999), skin fibroblasts (Garuti et al. 1997), kidney (Gascon-Barre et al. 2001), and the arterial wall (Shanahan et al. 2001). The enzyme catalyzes the 27-hydroxylation of cholesterol and 25-hydroxylation of vitamin D3 (Jones et al. 2014; Norlin and Wikvall 2007; Pikuleva 2006; Pikuleva et al. 1997; Tieu et al. 2012; Wikvall 2001). Bioactivation of cholesterol into bile acids is crucial for regulation of cholesterol homeostasis. The “classic” pathway of bile acid formation starts with a 7α-hydroxylation of cholesterol by CYP7A1 in the liver, while the “acidic” pathway starts with a hepatic or extrahepatic 27-hydroxylation by CYP27A1 (Norlin and Wikvall 2007). Formation of cholic acid requires insertion of a 12α-hydroxyl group catalyzed by CYP8B1. Oxysterols are precursors to bile acids, participate in cholesterol transport, and are known to affect the expression of several genes in cholesterol homeostasis. CYP27A1 is attached to the inner mitochondrial membrane and substrates appear to reach the active site through the membrane phase. The distance between the hydroxylation site and the end of the site chain is proportional to the regioselectivity of the enzyme (Dilworth et al. 1995).
The Cerebellar Ataxias and Hereditary Spastic Paraplegias
John W. Scadding, Nicholas A. Losseff in Clinical Neurology, 2011
Cholestanolosis (cerebrotendinous xanthomatosis) presents as a childhood-onset cerebellar ataxia with spasticity (which may be the prime feature), epilepsy, cognitive impairment, cataracts, neuropathy and xanthomas on tendons. Magnetic resonance scanning of the brain shows lesions of the dentate nuclei, brainstem and basal ganglia. The level of CSF protein is elevated and cholestanol levels are also increased as a result of an abnormality of bile salt synthesis; early treatment with chenodeoxycholic acid is partly effective. The condition is caused by mutations of the sterol 27-hydroxylase (CYP27A1) gene. Limited treatment is possible with chenodeoxycholic acid and pravastatin.
A novel mutation in the CYP27A1 gene in a family with cerebrotendinous xanthomatosis
Published in International Journal of Neuroscience, 2020
Yi Tang, Yanqiu Liu, Dan Li, Dongmei Guo, Yi Xing
Cerebrotendinous xanthomatosis (CTX) is an uncommon autosomal recessive sterol storage disorder caused by the abnormal deposition of cholestenol in the brain and other tissues. Thus, patients with CTX present various symptoms involving multiple systems, such as neurological deficits, juvenile cataracts, chronic diarrhea, tendon xanthomas, and atherosclerotic vascular disease [1]. The pathogenic gene is 27-hydroxylase (CYP27A1) gene, located on chromosome 2q33-qter [2] and encoding sterol 27-hydroxylase, a key enzyme in the bile acid biosynthesis pathway. Various mutations in all nine exons of CYP27A1 gene have been reported worldwide [3]. Half of the reported mutations are in exons 6-8, and a minor part of mutations are detected in exon 2 and 4 [3]. Here we report a Chinese family with two affected members (Figure 1). In our reported family, the parents of the patients are carriers of the CYP27A1 gene mutation, and 2/5 of their children, including a male and a female, are affected and show symptoms of CTX. This is consistent with autosomal recessive inheritance pattern. The genetic analysis demonstrated compound heterozygous mutations in CYP27A1 gene, including a novel mutation c.562C > T in exon 3.
Changes in hepatic phase I and phase II biotransformation enzyme expression and glutathione levels following atrazine exposure in female rats
Published in Xenobiotica, 2018
Arthur D. Zimmerman, Charles B. Breckenridge, Kun D. Yi, Pragati Sawhney Coder, Desiree Wanders, Robert L. Judd, Chad D. Foradori
The current study identified a large number of CYP enzymes which demonstrated altered mRNA expression after ATR treatment but have not previously been linked to ATR treatment. CYP2D2, CYP2C7, CYP2R1, CYP3A18 and CYP3A23/3A1 all showed increased expression after 4 and 8 days of ATR treatment compared to control, but by 14 days of ATR treatment, expression levels were back to control levels. These CYP isoforms are regulated following short-term ATR exposure and might be involved in the initial metabolism of or represent an adaptive response to ATR exposure. The expression of CYP17A1, an enzyme with 17-alpha-hydroxylase and 17,20-lyase activities that catalyzes the conversion of pregnenolone to dehydroepiandrosterone (DHEA) (Payne & Hales, 2004), was not statistically significantly elevated in our study. CYP27A1, which is known to perform the 27-hydroxylation of cholesterol, displayed an approximate two-fold increased expression on day 8 and 14 in the mid- and high-dose (50 and 100 mg/kg/day) groups.
Circadian rhythms and bile acid homeostasis: a comprehensive review
Published in Chronobiology International, 2020
Zaoqin Yu, Jinyu Yang, Dong Xiang, Guodong Li, Dong Liu, Chengliang Zhang
In humans, the bile acid pool is composed of primary bile acids, including cholic acid (CA) and chenodeoxycholic acid (CDCA), and secondary bile acids, including deoxycholic acid (DCA) and lithocholic acid (LCA) (Li and Apte 2015; Li and Chiang 2014). Primary bile acids are synthesized from cholesterol via two major pathways in hepatocytes, i.e. the classic pathway and alternative pathway (Figure 1). In humans, the classic pathway is responsible for about 90% of total bile acid production in the liver, generating CA and CDCA, which is considered the major bile acid biosynthetic pathway. Cholesterol 7α-hydroxylase (CYP7A1), which is the rate-limiting enzyme in the classic pathway, converts cholesterol into CDCA (Chiang 2009), and microsomal sterol 12α-hydroxylase (CYP8B1) mediates the production of CA. Intermediate 7α-hydroxy-4-cholestene-3-one (C4) is the common precursor for CA and CDCA and has been used as a surrogate serum marker for the rate of bile acid synthesis in humans (Axelson et al. 1988; Honda et al. 2007). In the alternative pathway, mitochondrial sterol 27-hydroxylase (CYP27A1) catalyzes the conversion of cholesterol into CDCA, which accounts for less than 10% of bile acid synthesis in humans. In contrast, the alternative pathway may be responsible for the synthesis of about 50% of bile acids in rodents (rat and mouse). Secondary bile acids are produced mainly through the conversion of primary bile acids by gut bacteria.
Related Knowledge Centers
- Bile Acid
- Inflammation
- Cytochrome P450
- Gene
- Mitochondrion
- Cholesterol
- Oxysterol
- Hydroxy Group
- 27-Hydroxycholesterol
- Macrophage