Genetic Aspects of Cortisol Hydroxylation in Guinea Pigs: Urinary Excretion and Production Rates of Cortisol and 2α-Hydroxycortisol1

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Abstract
The mode of inheritance of the ability to form hydroxylated derivatives of cortisol (polar corti-costeroids) in the guinea pig, with special emphasis given to 2[alpha]-hydroxy-cortisol, was studied. Two homozygous strains of short-haired English type guinea pigs differing greatly in this trait were crossed. The F1 generation exhibited polar corticosteroid excretion intermediate between that found in the parents but no significant difference in the excretion of cortisol. The F2 generation could be categorized (bringing the distribution of the F1 progeny into account) into 3 classes: low, medium and high hydroxycortisol excretors having a frequency consistent with the 1:2:1 genotypic ratio. Mating of a high excretor from the F2 generation with homozygous low excretors resulted in progeny of medium excretors. The fact that the ability to form hydroxycortisol derivatives is genetically determined suggests that the determination of urinary levels (or production rates) of these compounds may be useful in assessing the degree of homozygosity of guinea pig strains. Production rates of cortisol and 2[alpha]-hydroxycortisol were determined from the cumulative specific activities of the urinary steroids following injection of tracer doses of 4-C14-cortisol and H3-2[alpha]-hydroxycortisol. The production rates of 2[alpha]-hydroxycortisol in the low, high and medium excretors of the various genotypes were consistent with the results obtained from the urinary studies, demonstrating that the differences in the urinary levels are due to actual production rates and are not because of differ-ences in metabolic or renal clearance rates. The C14-specific activity of the 2[alpha]-hydroxycortisol was in all cases lower than that of the cortisol, indicating an extraperipheral source of 2[alpha]-hydroxycortisol such as adrenal secretion. The cortisol production rates were of the same order of magnitude in all genotypes.