TY  - CHAP
M1  - Book, Section
TI  - Pharmacogenetics
A1  - Kalow, Werner
A1  - Grant, Denis M.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Pharmacogenetics  has  been  defined  as  the  science  that  deals  with  pharmacologic  responses  and  their  modification  by  hereditary  influences.  Much  clinical  work  has  been  done  under  this  broad  label.  Variation  of  drug-metabolizing  enzymes,  responsible  for  a  large  section  of  pharmacogenetics,  represents  person-to-person  differences  within  the  chemical  defense  systems.  These  differences  and  the  variations  that  affect  susceptibility  to  infectious  diseases  (e.g.,  tuberculosis  and  malaria)  may  have  comparable  biologic  effects:  They  will  aid  the  survival  of  populations  exposed  to  toxins  or  to  infectious  agents,  respectively.The  history  and  scope  of  pharmacogenetics  have  been  outlined  briefly.  Various  chapters  in  this  book  might  have  been  classified  by  their  contents  as  part  of  pharmacogenetics  [e.g.,  glucose-6-phosphate  dehydrogenase  (G-6-PD)  deficiency]  but  they  are  treated  as  independent  entities  and  presented  on  their  own  merits.  This  chapter  on  pharmacogenetics  presents  three  selected  case  studies  that  are  of  unquestioned  clinical  importance  and,  at  the  same  time,  illustrate  a  wide  range  of  problems.Malignant  hyperthermia  (MH)  is  the  most  feared  complication  of  general  anesthesia,  observed  in  about  1:15,000  children  and  1:100,000  adults;  it  occurs  on  the  basis  of  genetic  predisposition  affecting  skeletal  muscle.  It  is  not  a  uniform  disease,  but  its  common  parameter  is  pathologic  elevation  of  ionized  calcium  in  the  sarcoplasm.  This  calcium  triggers  muscle  rigidity,  elevation  of  body  temperature,  acidosis,  tachycardia,  and  other  secondary  events.  Clinically,  an  MH  attack  is  most  frequently  triggered  by  halothane  and  succinylcholine;  for  diagnostic  purposes,  contractures  of  muscle  biopsy  specimens  on  exposure  to  caffeine  and/or  halothane  are  utilized.  An  equivalent  abnormality  in  pigs  is  caused  by  a  Cys  for  Arg615  substitution  in  the  ryanodine  receptor,  the  calcium  release  channel  of  the  sarcoplasmic  reticulum.  Predisposition  to  MH  in  humans  is  often  but  not  always  caused  by  the  same  mutation.In  the  1950s,  a  variant  (atypical)  form  of  butyrylcholinesterase  (BChE)  was  found  to  be  responsible  for  the  prolongation  of  action  of  the  muscle  relaxant  succinylcholine.  Any  physiological  function  of  BChE  is  still  not  known,  but  it  is  known  to  be  a  homotetramer  produced  by  a  single  gene  on  chromosome  3  at  q26.1-26.2.  Mutations  with  an  allele  frequency  of  0.017  in  Caucasians  may  affect  its  capacities  for  substrate  binding,  its  turnover  numbers,  or  both  combined  in  linkage  disequilibrium;  some  silent  variants  are  inactive,  and  some  represent  frameshift  mutations  with  absence  of  enzyme  protein.  Originally,  the  clinical  interest  in  BChE  deficiency  centered  on  the  prolonged  action  of  the  normally  short-acting  succinylcholine  when  given  during  anesthesia.  Of  recent  interest  is  the  metabolism  of  cocaine  by  BChE;  infusions  of  purified  BChE  promise  to  relieve  cocaine  toxicity,  particularly  when  the  drug  has  been  applied  in  multiple  doses  or  in  forms  designed  for  rapid  absorption.  Recent  areas  of  study  are  questions  of  a  role  of  BChE  in  Alzheimer  disease,  or  of  BChE  variants  as  contributors  to  the  Gulf  War  syndromes  because  of  abnormalities  of  pyridostigmine  action.A  genetic  polymorphism  now  known  to  affect  the  oxidative  biotransformation  of  debrisoquine,  sparteine,  and  over  60  other  therapeutic  agents  was  first  described  in  the  mid-1970s.  This  genetic  defect  affects  the  function  of  a  specific  isozyme  of  cytochrome  P450,  namely,  CYP2D6,  and  it  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/18
UR  - ommbid.mhmedical.com/content.aspx?aid=1181401595
ER  -