Pharmacogenetics of caffeine and caffeine-halothane contractures in biopsies of human skeletal muscle.
In vitro pharmacological responses of fresh biopsy specimens of human skeletal muscle were used as indicators of some intrinsic muscle properties. The measured parameters that were utilized for the current study were contractures induced in vitro by caffeine or by caffeine plus halothane. The opportunity to study such specimens arose from clinical testing for diagnosing the genetic predisposition to malignant hyperthermia, a potentially fatal complication of anaesthesia. The current analysis covers data from over 1,000 subjects, most of whom were clinical suspects and relatives of these. Responsiveness of the muscle specimens varied over two orders of magnitude. The frequency distribution curves suggest that the variation does not represent a continuum but that there are three or more clusters of functional variants. Muscle specimens from males were on average more responsive to caffeine than were those from females. Correlations within father-son and brother-brother pairs indicated complete heritability of responsiveness; this might have been expected but the surprise was a lack of correlation within mother-daughter pairs. There was an intermediate correlation in father-daughter pairs. The sex difference in heritability could be due to gender-related modifying genes or due to secondary modification of the muscle response in females by sex-related, perhaps hormonal factors. Among the effects of age appeared to be poor development in early childhood of the potentiation of the caffeine contracture by halothane.
Kalow
W
W
Department of Pharmacology, University of Toronto, Ontario, Canada.
Sharer
S
S
Britt
B
B
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D006221:Halothane / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008305:Malignant Hyperthermia / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects* / Q000235:genetics; D012727:Sex Characteristics
D002110:Caffeine; D006221:Halothane