Alternative titles; symbols
HGNC Approved Gene Symbol: CYP2B6
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:40,991,282-41,018,398 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | {Efavirenz central nervous system toxicity, susceptibility to} | 614546 | 3 | |
| Efavirenz, poor metabolism of | 614546 | 3 |
Miles et al. (1988) reported the isolation of cDNA clones that seemed, on the basis of their sequence homology to the rat P450IIB1 cDNA, to be encoded by part of the human P450IIB subfamily. Evidence of alternative splicing at the CYP2B locus was presented. Yamano et al. (1989) demonstrated 2 anomalous cDNAs derived from the CYP2B locus on chromosome 19.
Santisteban et al. (1988) were unable to demonstrate directly that either P450IIA (CYP2A; see 122720) or IIB is inducible by phenobarbital in man. However, they showed that members of both gene subfamilies are inducible by phenobarbital in the marmoset monkey.
Thum and Borlak (2000) investigated the gene expression of major human cytochrome P450 genes in various regions of explanted hearts from 6 patients with dilated cardiomyopathy and 1 with transposition of the arterial trunk and 2 samples of normal heart. mRNA for cytochrome 2B6 was predominantly expressed in the right ventricle. A strong correlation between tissue-specific gene expression and enzyme activity was found. Thum and Borlak (2000) concluded that their findings showed that expression of genes for cytochrome P450 monooxgenases and verapamil metabolism are found predominantly in the right side of the heart, and suggested that this observation may explain the lack of efficacy of certain cardioselective drugs.
Mizukami et al. (1983) determined the structure of a rat phenobarbital-inducible P-450 gene. The gene spans about 14 kb and has 8 introns. The putative transcription start site is located 30 bp upstream of the ATG initiation codon and a TATA-like sequence is present 27 bp farther 5-prime-ward. The 3-prime end contains a putative polyadenylation signal 25 to 26 bp upstream of the poly(A) attachment site. Mizukami et al. (1983) concluded that the gene they sequenced is P-450e (Cyp2b2) or a similar gene. Presumably, all P-450 genes have a similar structure.
Using a cloned cDNA that codes for a human ortholog of the phenobarbital-inducible cytochrome P450IIB subfamily in rodents, Santisteban et al. (1988) localized the CYP2B gene(s) to 19cen-q13.3 by Southern blot hybridization to DNA extracted from a panel of human-rodent somatic cell hybrids. The CYP2A locus is also located on chromosome 19. Other members of the P450II family are located on chromosome 10 (2C) and chromosome 22 (2D).
By Southern blot analysis of human-rodent somatic cell hybrids, Miles et al. (1988) established the chromosomal localization of the CYP2B gene subfamily to be 19q12-19q13.2, close to the location of CYP2A. Rat chromosome 1 shows homology to mouse chromosome 7 and human chromosome 19 and contains the rat P450IIB genes. Southern blot analysis indicated the distinctness of the CYP2A and CYP2B clusters. Miles et al. (1988) used RFLPs of these loci to establish the linkage relationships.
CYP2B is in the same NotI fragment as CYP2A (Spurr, 1988). Although CYP2A and CYP2B map to the same 350-kb pulsed field gel electrophoresis fragment, recombination between them was observed by Walsh et al. (1989), suggesting that they are separated by a recombination hotspot. Yamano et al. (1989) confirmed the assignment to chromosome 19 using the somatic cell hybrid method. By fluorescence in situ hybridization, Trask et al. (1993) assigned the CYP2B gene to 19q13.2.
Efavirenz, an effective antiretroviral agent used in the treatment of human immunodeficiency virus (HIV; see 609423) infection, is associated with central nervous system side (CNS) effects (see 614546). Population differences in pharmacokinetics and treatment response to the drug are known. Haas et al. (2004) examined associations between CNS side effects and efavirenz plasma concentration-time profiles and polymorphisms in several genes, including CYP2B6, in 157 American HIV-infected patients. They found that homozygosity for a nonsynonymous CYP2B6 SNP, 516G-T (Q172H; 123930.0001, rs3745274), was present in 20% of African Americans compared with only 3% of European Americans and was associated with higher efavirenz exposure in plasma (p less than 0.0001). The median 24-hour area under the curve of efavirenz was about 3-fold higher in 516T homozygotes than in 516G homozygotes, and was intermediate in 516GT heterozygotes, regardless of ethnicity, suggesting a gene dosage effect. Among all patients, CNS side effects at week 1 were associated with 516T (p = 0.036). There were no significant immunologic or virologic differences for polymorphisms in any of the genes studied. Haas et al. (2004) concluded that interindividual differences in drug metabolism may, in part, explain susceptibility to efavirenz CNS side effects.
The Q172H and K262R (123930.0002) substitutions define the CYP2B6*6 allele. In a study of 35 Japanese patients taking efavirenz, Tsuchiya et al. (2004) found that 2 patients who were homozygous for the *6 allele had significantly higher plasma efavirenz levels compared to those who were heterozygous for the *6 allele or those without the *6 allele.
Blievernicht et al. (2007) used multiplex PCR and MALDI-TOF mass spectrometry to genotype 15 SNPs of CYP2B6.
Watanabe et al. (2010) expressed wildtype CYP2B6 and 26 CYP2B6 variants in COS-7 cells and assessed kinetic parameters against 2 substrates, selegiline and 7-ethoxy-4-trifluoromethylcoumarin (7-EFC). They found that 2 variants, CYP2B6.10 and CYP2B6.14, had significantly lower Vmax/Km values for selegiline N-demethylation compared with wildtype CYP2B6. The kinetic parameters for 9 other variants could not be determined because they were inactive in the deethylation of 7-EFC and the N-demethylation/N-depropaglyation of selegiline.
In a genotypic study for prevention of mother-to-child transmission of HIV-1 in Rwandese women, Radloff et al. (2013) identified 4 functional missense variants in the CYP2B6 gene (123930.0003-123930.0006) that were demonstrated in cellular studies to cause a loss of enzyme function with the substrates efavirenz and bupropion. These variants were found in 8 of 39 samples. All variants were part of larger haplotypes, and Radloff et al. (2013) proposed 5 new alleles termed CYP2B6*33 to CYP2B6*27.
By genotyping 100 healthy Mongolians, Davaalkham et al. (2009) found that 7% of Mongolians were homozygous for the T allele of 516G-T, whereas 64% were homozygous for the G allele. They noted that the overall CYP2B6 allele distribution was comparable to that in Japanese, Korean, and Han Chinese populations.
Radloff et al. (2013) determined that the frequency of the CYP2B6*6 allele was 28% among 39 Rwandese women studied.
Paolini et al. (1999) found significant increases in the carcinogen-metabolizing enzymes CYP1A1 (108330), CYP1A2 (124060), CYP3A (124010), CYP2B, and CYP2A in the lungs of rats supplemented with high doses of beta-carotene. The authors suggested that correspondingly high levels of CYPs in humans would predispose an individual to cancer risk from the widely bioactivated tobacco-smoke procarcinogens, thus explaining the cocarcinogenic effect of beta-carotene in smokers.
Haas et al. (2004) studied 157 American HIV-infected patients and found that homozygosity for a nonsynonymous SNP in CYP2B6, 516G-T (rs3745274), which results in a gln172-to-his (Q172H) substitution, was present in 20% of African Americans compared with only 3% of European Americans and was associated with higher efavirenz exposure in plasma (p less than 0.0001) (see 614546). The median 24-hour area under the curve of efavirenz was about 3-fold higher in 516T homozygotes than in 516G homozygotes, and was intermediate in 516GT heterozygotes, regardless of ethnicity, suggesting a gene dosage effect. Among all patients, CNS side effects at week 1 were associated with 516T (p = 0.036). Higher efavirenz concentrations had no effect on HIV viral load.
Carr et al. (2010) determined plasma efavirenz concentrations in 219 HIV-positive Chilean patients and identified 11 CYP2B6 SNPs that were significantly associated with drug concentrations. Of these, only 516G-T (p = 5.6 x 10(-20)) was exonic. However, a composite model in which 516G-T was combined 2 other SNPs was more strongly associated with efavirenz plasma concentrations than 516G-T alone.
Elens et al. (2010) studied 50 HIV-infected patients from Belgium and confirmed that minimum trough plasma level concentrations of efavirenz were associated with CYP2B6 allelic status. They also found that cell-associated concentrations of efavirenz were associated with CYP2B6 516G-T. Elens et al. (2010) concluded that knowledge of CYP2B6 genetic status should be taken into account for efavirenz treatment.
A lys262-to-arg (K262R) substitution resulting from a c.785A-G transition in exon 5 of the CYP2B6 gene, together with Q172H (123930.0001), defines the CYP2B6*6 allele. In a study of 35 Japanese patients taking efavirenz, Tsuchiya et al. (2004) found that 2 patients who were homozygous for the *6 allele had significantly higher plasma efavirenz levels (see 614546) compared to those who were heterozygous for the *6 allele or those without the *6 allele. Three additional patients with high plasma levels of the drug were also found to be homozygous for the *6 allele. Tsuchiya et al. (2004) suggested that patients who are homozygous for this allele should take lower doses of efavirenz to reduce drug toxicity.
Radloff et al. (2013) determined that the frequency of the CYP2B6*6 allele was 28% among 39 Rwandese women studied.
By sequencing the CYP2B6 gene in a Rwandese cohort enrolled in a study of prevention of mother-to-child transmission of HIV-1, Radloff et al. (2013) identified a c.329G-T transversion in exon 2, resulting in a gly110-to-val (G110V) substitution. The variant was part of a haplotype (CYP2B6*35) found in 3 of 39 different samples. Expression of the variant in COS-1 cells showed up to 80% reduction in protein expression compared to wildtype. Measurement of enzymatic activity of the variant protein with the substrates efavirenz (see 614546) and bupropion showed no detectable metabolites, consistent with a loss of function. Molecular dynamic simulations indicated that the affected residue was close to the enzyme's active site, and interaction energy analysis suggested decreased stability of the ligand-protein complex.
By sequencing the CYP2B6 gene in a Rwandese cohort enrolled in a study of prevention of mother-to-child transmission of HIV-1, Radloff et al. (2013) identified a c.341T-C transition in exon 3 of the CYP2B6 gene, resulting in an ile114-to-thr (I114T) substitution. The variant was part of a haplotype (CYP2B6*35) found in 3 of 39 different samples. Expression of the variant in COS-1 cells resulted in 70% increased protein expression compared to wildtype. Measurement of enzymatic activity of the variant protein with the substrates efavirenz (see 614546) and bupropion showed no detectable metabolites, consistent with a loss of function. Molecular dynamic simulations indicated that the affected residue was close to the enzyme's active site, and interaction energy analysis suggested decreased stability of the ligand-protein complex.
By sequencing the CYP2B6 gene in a Rwandese cohort enrolled in a study of prevention of mother-to-child transmission of HIV-1, Radloff et al. (2013) identified a c.548T-G transversion in exon 4 of the CYP2B6 gene, resulting in a val183-to-gly (V183G) substitution. The variant was part of a haplotype (CYP2B6*37) found in 1 of 39 different samples. Expression of the variant in COS-1 cells resulted in up to 80% reduction in protein expression compared to wildtype. Measurement of enzymatic activity of the variant protein with the substrates efavirenz (see 614546) and bupropion showed no detectable metabolites, consistent with a loss of function. Molecular dynamic simulations indicated that the affected residue was close to the enzyme's active site, and interaction energy analysis suggested decreased stability of the ligand-protein complex.
By sequencing the CYP2B6 gene in a Rwandese cohort enrolled in a study of prevention of mother-to-child transmission of HIV-1, Radloff et al. (2013) identified a c.637T-C transition in exon 4 of the CYP2B6 gene, resulting in a phe213-to-leu (F213L) substitution. The variant was part of a haplotype found in 1 of 39 samples. Expression of the variant in COS-1 cells resulted in up to 80% reduction in protein expression compared to wildtype. Measurement of enzymatic activity of the variant protein with the substrate efavirenz (see 614546) showed no detectable metabolites, consistent with a loss of function. Activity against bupropion was also decreased, to about 40% of wildtype. Molecular dynamic simulations indicated that the affected residue was close to the enzyme's active site, and interaction energy analysis suggested decreased stability of the ligand-protein complex.
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Carr, D. F., la Porte, C. J. L., Pirmohamed, M., Owen, A., Cortes, C. P. Haplotype structure of CYP2B6 and association with plasma efavirenz concentrations in a Chilean HIV cohort. J. Antimicrob. Chemother. 65: 1889-1893, 2010. [PubMed: 20639527] [Full Text: https://doi.org/10.1093/jac/dkq260]
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