Pharmacogenetics of methylation: Relationship to drug metabolism

doi:10.1016/S0009-9120(88)80002-X

Clinical Biochemistry

Volume 21, Issue 4, August 1988, Pages 201-210

https://doi.org/10.1016/S0009-9120(88)80002-X Get rights and content

Pharmacogenetics is the study of inherited variation in drug response. Genetic differences in drug metabolism are the most common causes for inherited variations in drug response or adverse reactions to medications. Methyl conjugation is an important pathway in the biotransformation of many drugs. Experiments performed during the past decade showed that individual variations in the activities of enzymes that catalyze S-methylation, O-methylation and N-methylation are under genetic control in human tissue. These inherited variations are responsible for individual differences in metabolism, effect, and toxicity of drugs that undergo methyl conjugation. The approach used to study the pharmacogenetics of methylation may also be applicable to the study of inherited variations in other pathways of drug metabolism.

References (65)

WeinshilboumRM
“Methylator status” and assessment of variation in drug metabolism
Trends in Pharmacol Sci
(1980)
RaymondFA et al.
Microassay of human erythrocyte catechol-O-methyltransferase: Removal of inhibitory calcium ion with chelating resin
Clin Chim Acta
(1975)
WeinshilboumRM et al.
Human erythrocyte thiopurine methyltransferase: Radiochemical microassay and biochemical properties
Clin Chim Acta
(1978)
WeinshilboumRM et al.
Human erythrocyte thiol methyltransferase: Radiochemical microassay and biochemical properties
Clin Chim Acta
(1979)
Van LoonJA et al.
Human erythrocyte histamine N-methyltransferase: Radiochemical microassay and biochemical properties
Clin Chim Acta
(1985)
PerrettD et al.
Studies on D-penicillamine metabolism in cystinuria and rheumatoid arthritis: Isolation of S-methyl-D-penicillamine
Biochem Pharmacol
(1976)
WoodsonLC et al.
Human kidney thiopurine methyltransferase: Purification and biochemical properties
Biochem Pharmacol
(1983)
RemyCN
Metabolism of thiopyrimidines and thiopurines: S-methylation with S-adenosylmethionine transmethylase and catabolism in mammalian tissue
J Biol Chem
(1963)
BremerJ et al.
Enzymatic methylation of foreign sulfhydryl compounds
Biochim Biophys Acta
(1961)
LennardL et al.
Are children with lymphoblastic leukemia given enough 6-mercaptopurine?
The Lancet
(1987)

OtternessDM et al.

Thiopurine methyltransferase: Mouse kidney and liver assay conditions, biochemical properties and strain variation

Biochem Pharmacol

(1985)

AxelrodJ et al.

Enzymatic O-methylation of epinephrine and other catechols

J Biol Chem

(1958)

AxelrodJ et al.

Phenol-O-methyltransferase

Biochim Biophys Acta

(1968)

PazmiñoPA et al.

Human erythrocyte phenol-O-methyltransferase: Radiochemical microassay and biochemical properties

Clin Chim Acta

(1978)

CrevelingCR et al.

Immunological characterization of catechol-O-methyltransferase

WeinshilboumR

The therapeutic revolution

Clin Pharmacol Ther

(1987)

WeinshilboumRM

Human pharmacogenetics: An introduction

Fed Proc

(1984)

WeinshilboumRM

Human pharmacogenetics of methyl conjugation

Fed Proc

(1984)

HisW

Ueber das Stoffwechselproduct des Pyridins

Arch Exp Pathol Pharmakol

(1884)

Cavalli-SforzaLL et al.

The Genetics of Human Populations

(1971)

VogelF et al.

Human Genetics: Problems and Approaches

(1979)

HopkinsonDA et al.

Genetical studies on human red cell acid phosphatase

Human Genet

(1964)

DrummerOH et al.

Demonstration of a S-methyl metabolite of captopril in patients undergoing chronic captopril therapy

Clin Exp Pharmacol Physiol

(1982)

PatersonARP et al.

6-Thiopurines, antineoplastic and immunosuppressive agents

OtternessDM et al.

Mouse liver thiol methyltransferase: Assay conditions, biochemical properties and strain variation

Drug Metab Disposit

(1986)

WoodsonLC et al.

Thiopurine methyltransferase: Aromatic thiol substrates and inhibition by benzoic acid derivatives

Mol Pharmacol

(1983)

AmesMM et al.

Thiopurine methyltransferase: Structure-activity relationships for benzoic acid inhibitors and thiophenol substrates

J Med Chem

(1986)

KeithRA et al.

Human erythrocyte membrane thiol methyltransferase: S-Methylation of captopril, N-acetylcysteine and 7-α-thiospirolactone

Drug Metab Disposit

(1984)

KeithRA et al.

S-Methylation of D- and L-penicillamine by human erythrocyte membrane thiol methyltransferase

Drug Metab Disposit

(1985)

WeinshilboumRM et al.

Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity

Am J Human Genet

(1980)

KeithRA et al.

Thiol methylation pharmacogenetics: Heritability of human erythrocyte thiol methyltransferase activity

Clin Pharmacol Ther

(1983)

LennardL et al.

Thiopurine pharmacogenetics in leukemia: Correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations

Clin Pharmacol Ther

(1987)

Cited by (50)

The thiol methyltransferase activity of TMT1A (METTL7A) is conserved across species
2024, Chemico-Biological Interactions
Although few resistance mechanisms for histone deacetylase inhibitors (HDACis) have been described, we recently demonstrated that TMT1A (formerly METTL7A) and TMT1B (formerly METTL7B) can mediate resistance to HDACis with a thiol as the zinc-binding group by methylating and inactivating the drug. TMT1A and TMT1B are poorly characterized, and their normal physiological role has yet to be determined. As animal model systems are often used to determine the physiological function of proteins, we investigated whether the ability of these methyltransferases to methylate thiol-based HDACis is conserved across different species. We found that TMT1A was conserved across rats, mice, chickens, and zebrafish, displaying 85.7%, 84.8%, 60.7%, and 51.0% amino acid sequence identity, respectively, with human TMT1A. Because TMT1B was not found in the chicken or zebrafish, we focused our studies on the TMT1A homologs. HEK-293 cells were transfected to express mouse, rat, chicken, or zebrafish homologs of TMT1A and all conferred resistance to the thiol-based HDACIs NCH-51, KD-5170, and romidepsin compared to empty vector-transfected cells. Additionally, all homologs blunted the downstream effects of HDACi treatment such as increased p21 expression, increased acetylated histone H3, and cell cycle arrest. Increased levels of dimethylated romidepsin were also found in the culture medium of cells transfected to express any of the TMT1A homologs after a 24 h incubation with romidepsin compared to empty-vector transfected cells. Our results indicate that the ability of TMT1A to methylate molecules is conserved across species. Animal models may therefore be useful in elucidating the role of these enzymes in humans.
Translating Pharmacogenomic Research to Therapeutic Potentials (Bench to Bedside)
2022, Comprehensive Pharmacology
Standard prescribing practice follows an empirical model, trial-and-error, and uses subpopulation data to predict efficacy and potential side effects. This traditional practice is now changed by new genetic knowledge. Pharmacogenomics, the study of individual genetic variation affecting drug pharmacokinetics and pharmacodynamics, has the potential to improve prescribing practice by personalizing drug selection. The rapid and clinically significant advances in basic and clinical pharmacogenomics research have created a knowledge gap between bench and bedside. This knowledge is new, complex and growing fast, and its implementation is critical in current clinical practice with a growing number of drug therapies. There are many challenges and opportunities to the universal bedside implementation of pharmacogenomics. However, rapid progress is happening and in some clinical practices pharmacogenomics is now routine practice. This chapter attempts to provide the necessary basic knowledge to understand different aspects of clinical pharmacogenomics, be able to interact with ordering and test results, understand the implications for specific drug selection and be able to apply those results for patient care.
Xenobiotic transport and metabolism in the human brain
2021, NeuroToxicology
Citation Excerpt :
Methylation of these substrates is classified as N-methylation (amines), O-methylation (phenolic groups of catechols), and S-methylation (thiol groups). Methyltransferase (MET) conjugation is important in the metabolism of many drugs, xenobiotics, neurotransmitters (dopamine, norepinephrine, and histamine), hormones, and the activation of β-carbonyls in the CNS (Gearhart et al., 1997; Relling et al., 1999; Weinshilboum, 1988). The brain expresses certain METs, such as N-MET, O-MET, and S-MET.
Organisms have metabolic pathways responsible for eliminating endogenous and exogenous toxicants. Generally, we associate the liver par excellence as the organ in charge of detoxifying the body; however, this process occurs in all tissues, including the brain. Due to the presence of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), the Central Nervous System (CNS) is considered a partially isolated organ, but similar to other organs, the CNS possess xenobiotic transporters and metabolic pathways associated with the elimination of xenobiotic agents. In this review, we describe the different systems related to the detoxification of xenobiotics in the CNS, providing examples in which their association with neurodegenerative processes is suspected. The CNS detoxifying systems include carrier-mediated, active efflux and receptor-mediated transport, and detoxifying systems that include phase I and phase II enzymes, as well as those enzymes in charge of neutralizing compounds such as electrophilic agents, reactive oxygen species (ROS), and free radicals, which are products of the bioactivation of xenobiotics. Moreover, we discuss the differential expression of these systems in different regions of the CNS, showing the different detoxifying needs and the composition of each region in terms of the cell type, neurotransmitter content, and the accumulation of xenobiotics and/or reactive compounds.
5-HTTLPR and COMT Val158Met are not associated with alexithymia: New evidence and meta-analyses
2019, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
The G allele of rs25531 is always in phase with the L allele of 5-HTTLPR, and the SS/SA and SALG haplotypes are related to lower 5-HTT expression as compared with the LALA haplotype (Kosek et al., 2009). The catechol-O-methyltransferase (COMT) enzyme is a critical enzyme for degrading dopamine (Liang et al., 2017; Weinshilboum, 1988). Within the COMT gene, a functional polymorphism in codon 158 (Val158Met), leading to an amino acid substitution of valine (Val) for methionine (Met), leads to the Met/Met genotype showing 40% less enzymatic activity than the Val/Val genotype (Bilder et al., 2004; J. Chen et al., 2004; Lachman et al., 1996).
Alexithymia refers to the difficulties in identifying and describing one's own emotions, lacking of imagination, and an externally oriented thinking style. Studies up to date have examined the associations of 5-HTTLPR and COMT Val158Met polymorphisms with alexithymia. However, the previous findings were mixed.
We replicated the associations by scoring on alexithymia with the 20-item Toronto Alexithymia Scale and genotyping the polymorphisms of 5-HTTLPR and COMT Val158Met in a large population of college students (N = 1698). Moreover, we also meta-analyzed the associations with five samples (N = 7517) for the 5-HTTLPR and with five samples (N = 2186) for the COMT Val158Met.
Neither the replicated study nor the meta-analyses indicated the 5-HTTLPR and COMT Val158Met were associated with alexithymia.
The findings suggest that the 5-HTTLPR and COMT Val158Met polymorphisms are not associated with alexithymia. However, genetic-environmental studies with different ethnicity and psychopathology should be carried in future.
Methyltransferases
2018, Comprehensive Toxicology: Third Edition
Methyltransferases represent a group of enzymes, most which, over 95%, use S-adenosyl-l-methionine (AdoMet) as a methyl donor. The basic methyl transfer reaction is the catalytic attack of a nucleophile (carbon, oxygen, nitrogen, or sulfur) on a methyl group to form methylated derivatives of proteins, lipids, polysaccharides, nucleic acids, and various small molecules. Methyl conjugation is an important pathway in the metabolism of many drugs and xenobiotic compounds, as well as endogenous neurotransmitters and hormones. Methylation is also fundamental for the regulation of gene transcription. AdoMet-dependent methyltransferase enzymes are an example of convergent evolution, a series of enzymes with very different overall structures but with similar properties at the active site, which enables catalysis of the methyl transfer reaction (Schluckebier et al., 1995; Schubert et al., 2003). There are five structurally distinct families of AdoMet-dependent methyltransferases, each family representing a series of enzymes with structurally similar active sites and, between methyltransferase classes, different structures with similar functions (Schubert et al., 2003). The Enzyme Commission (EC) has allocated numbers to over 250 methyltransferases: the N-methylation of pyridine, documented in the late 19th century, was the first methyl conjugation reaction to be described (His, 1887; Weinshilboum et al., 1999), and tellurite methyltransferase (EC 2.1.1.265) will almost certainly not be the last.
The impacts of Val158Met in Catechol-O-methyltransferase (COMT) gene on moral permissibility and empathic concern
2017, Personality and Individual Differences
Citation Excerpt :
Thus, in this study we investigated whether Catechol-O-methyltransferase gene, which modulates levels of dopamine in the brain, underpins the individual differences in moral permissibility. The Catechol-O-methyltransferase (COMT) enzyme degrades dopamine in the prefrontal cortex (Weinshilboum, 1988). This enzyme is encoded by COMT gene.
Dopamine levels in the brain influence emotional experiences and empathic responses to others' misfortune. Inspired by roles of Catechol-O-methyltransferase (COMT) in dopamine degradation and the link between moral judgment and empathic responses, this study investigated to what extent the Val158Met polymorphism of COMT gene contributes to individual differences in moral permissibility and empathic dispositions. One thousand two hundred and seventy-two Chinese Han college students, who were differentiated with the COMT Val158Met (rs4680) polymorphism, rated permissibility of harm in moral dilemmas and scored their empathic dispositions with Interpersonal Reactivity Index. The results showed a significant association between COMT Val158Met and the moral permissibility of committing harm. Individuals with the Val/Val genotype, which is associated with lower levels of dopamine, endorsed impersonal harm as more impermissible than those with the Val/Met and Met/Met genotypes. Results also showed that individuals with the Val/Val genotype showed higher empathic concern for others' misfortune. The findings provide the first evidence for the link between COMT gene and the moral permissibility, highlighting the roles of dopamine in social cognition.

View all citing articles on Scopus

View full text

Pharmacogenetics of methylation: Relationship to drug metabolism

Trends in Pharmacol Sci

Clin Chim Acta

Clin Chim Acta

Clin Chim Acta

Clin Chim Acta

Biochem Pharmacol

Biochem Pharmacol

J Biol Chem

Biochim Biophys Acta

The Lancet

Biochem Pharmacol

J Biol Chem

Biochim Biophys Acta

Clin Chim Acta

The therapeutic revolution

Clin Pharmacol Ther

Human pharmacogenetics: An introduction

Fed Proc

Human pharmacogenetics of methyl conjugation

Fed Proc

Ueber das Stoffwechselproduct des Pyridins

Arch Exp Pathol Pharmakol

The Genetics of Human Populations

Human Genetics: Problems and Approaches

Genetical studies on human red cell acid phosphatase

Human Genet

Demonstration of a S-methyl metabolite of captopril in patients undergoing chronic captopril therapy

Clin Exp Pharmacol Physiol

6-Thiopurines, antineoplastic and immunosuppressive agents

Mouse liver thiol methyltransferase: Assay conditions, biochemical properties and strain variation

Drug Metab Disposit

Thiopurine methyltransferase: Aromatic thiol substrates and inhibition by benzoic acid derivatives

Mol Pharmacol

Thiopurine methyltransferase: Structure-activity relationships for benzoic acid inhibitors and thiophenol substrates

J Med Chem

Human erythrocyte membrane thiol methyltransferase: S-Methylation of captopril, N-acetylcysteine and 7-α-thiospirolactone

Drug Metab Disposit

S-Methylation of D- and L-penicillamine by human erythrocyte membrane thiol methyltransferase

Drug Metab Disposit

Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity

Am J Human Genet

Thiol methylation pharmacogenetics: Heritability of human erythrocyte thiol methyltransferase activity

Clin Pharmacol Ther

Thiopurine pharmacogenetics in leukemia: Correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations

Clin Pharmacol Ther