Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.

/pdf/sequence-diversity-in-cyp3a-promoters-and-characterization-1lyuqaeh8f.pdf

Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.

It is well recognized that different patients respond in different ways to the same medication. These differences are often greater among members of a population than they are within the same person at different times (or between monozygotic twins).1 The existence of large population differences with small intrapatient variability is consistent with inheritance as a determinant of drug response; it is estimated that genetics can account for 20 to 95 percent of variability in drug disposition and effects.2 Although many nongenetic factors influence the effects of medications, including age, organ function, concomitant therapy, drug interactions, and the nature of the . . .

https://www.nejm.org/doi/pdf/10.1056/NEJMra020526

Pharmacogenomics — Drug Disposition, Drug Targets, and Side Effects

Genetic contribution to variable human CYP3A-mediated metabolism

Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.

Polymorphism of human cytochrome P450 enzymes and its clinical impact

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(02)07276-8.pdf

Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study.

Objective

To determine the existence of mutant and variant CYP3A4 alleles in three racial groups and to assess functions of the variant alleles by complementary deoxyribonucleic acid (cDNA) expression.



Methods

A bacterial artificial chromosome that contains the complete CYP3A4 gene was isolated and the exons and surrounding introns were directly sequenced to develop primers to polymerase chain reaction (PCR) amplify and sequence the gene from lymphocyte DNA. DNA samples from Chinese, black, and white subjects were screened. Mutating the affected amino acid in the wild-type cDNA and expressing the variant enzyme with use of the baculovirus system was used to functionally evaluate the variant allele having a missense mutation.



Results

To investigate the existence of mutant and variant CYP3A4 alleles in humans, all 13 exons and the 5′-flanking region of the human CYP3A4 gene in three racial groups were sequenced and four alleles were identified. An AG point mutation in the 5′-flanking region of the human CYP3A4 gene, designated CYP3A4*1B, was found in the three different racial groups. The frequency of this allele in a white population was 4.2%, whereas it was 66.7% in black subjects. The CYP3A4*1B allele was not found in Chinese subjects. A second variant allele, designated CYP3A4*2, having a Ser222Pro change, was found at a frequency of 2.7% in the white population and was absent in the black subjects and Chinese subjects analyzed. Baculovirus-directed cDNA expression revealed that the CYP3A4*2 P450 had a lower intrinsic clearance for the CYP3A4 substrate nifedipine compared with the wild-type enzyme but was not significantly different from the wild-type enzyme for testosterone 6β-hydroxylation. Another rare allele, designated CYP3A4*3, was found in a single Chinese subject who had a Met445Thr change in the conserved heme-binding region of the P450.



Conclusions

These are the first examples of potential function polymorphisms resulting from missense mutations in the CYP3A4 gene. The CYP3A4*2 allele was found to encode a P450 with substratedependent altered kinetics compared with the wild-type P450.



Clinical Pharmacology & Therapeutics (2000) 67, 48–56; doi: 10.1067/mcp.2000.104391

CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity.

A High-Throughput Screen to Identify Inhibitors of Aromatase (CYP19)

Analysis of drug transport and metabolism in cell monolayer systems that have been modified by cytochrome P4503A4 cDNA-expression.

The invention pertains to cynomologous monkey P-glycoproteins and related P-glycoproteins which include cynomologous-specific amino acids, as well as nucleic acids which encode those polypeptides. The present invention also includes fragments and biologically functional variants of the cynomologous monkey P-glycoprotein. The invention further relates to methods of using such cynomologous monkey P-glycoprotein nucleic acids and polypeptides, especially in methods for determining bioavailability of drugs and for screening for inhibitors of cynomologous PGP. Also included are cynomologous PGP inhibitors which inhibit cynomologous PGP activity by inhibiting the expression or function of cynomologous PGP.

P-glycoproteins from macaca fascicularis and uses thereof

L'invention concerne des P-glycoproteines de singe cynomolgus et des P-glycoproteines associees qui comprennent des acides amines specifiques dudit singe cynomolgus, ainsi que des acides nucleiques qui codent ces polypeptides. La presente invention a egalement trait a des fragments et des variants biologiquement fonctionnels de la P-glycoproteine du singe cynomolgus, ainsi qu'a des methodes d'utilisation de tels polypeptides et acides nucleiques de ladite P-glycoproteine, notamment des methodes de determination de la biodisponibilite de medicaments et de criblage d'inhibiteurs de ladite P-glycoproteine. Cette invention concerne aussi des inhibiteurs de ladite P-glycoproteine qui inhibent l'activite de celle-ci par inhibition de l'expression ou de la fonction de ladite P-glycoproteine.

Penny J. Stocker

Papers

CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity.

A High-Throughput Screen to Identify Inhibitors of Aromatase (CYP19)

Analysis of drug transport and metabolism in cell monolayer systems that have been modified by cytochrome P4503A4 cDNA-expression.

P-glycoproteins from macaca fascicularis and uses thereof

P-glycoproteines provenant de macaca fascicularis et utilisations correspondantes