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dimorphism - Sexual Dimorphism in the Liver Impact on drug...

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Sexual Dimorphism in the Liver Impact on drug metabolism, disease and cancer Arlin Rogers MIT Division of Comparative Medicine BE.450 April 25, 2005
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Gender differences in hepatic function • Lipid metabolism – Microsomal (smooth endoplasmic reticulum) – Mitochondrial – Peroxisomal • Steroid metabolism – Sex steroids and other cholesterol derivatives • Energy production – Females have higher mitochondrial function and metabolic activity
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Sex and the single rat (liver) Rats exhibit highest liver sexual dimorphism among tested species Females sleep longer when given hexabarbital (1937) Gonadectomy or exogenous steroids affect drug metabolism (1950’s) Classical species used in toxicology studies Skewed results??
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Liver dimorphism in non-rats • Mice – Exhibit dimorphism in Cyp genes, but some reversed in gender specificity vs. rat – Less pronouced differences than in rat • Other small animals – Dimorphism shown, but not pronounced • Primates (non-human and human) – Differences in drug metabolism between sexes known – But no gender-dimorphic CYP 450 genes shown yet – Individual variation masks small gender differences
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Mechanisms of liver dimorphism Growth hormone periodicity – GH is the greatest determinant of liver dimorphism • Sex steroids – Determine GH periodicity by indirect means – Direct action on liver? Liver expresses androgen, estrogen and progesterone receptors • Imprinting – Neonatal – Peripubertal • Hepatocyte nuclear factors
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Growth hormone regulation GH secreted by pituitary Regulated by neuropeptides from neurons in the hypothalamus Positive feedforward peptides growth hormone-releasing hormone (GHRH) – ghrelin Negative feedback peptide – somatostatin – inhibits GH release by pituitary somatotrophes until a certain threshold is exceeded
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Sex steroids and GH regulation Both androgens and estrogens stimulate GHRH and ghrelin secretion – Hypothalamic arcuate nucleus neurons bear both androgen receptors (AR) and estrogen receptors (ER) Only androgens stimulate somatostatin secretion Hypothalamic periventricular nucleus neurons only AR Net effect of sex steroids on GH secretion: – Females: frequent unpredictable release of submaximal GH from pituitary – Males: diurnally regular large GH boluses followed by long nadirs with undetectable serum GH
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Control of GH secretion (males) Figure removed for copyright reasons.
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GH periodicity and gender- specific CYP gene expression Rat Cyp2c11 is male- predominant Cyp2c12 is female Regular GH cycle in males stimulates Cyp2c11 via Jak2/Stat5b signaling Interpeak period determines dimorphic gene expression, not wave amplitude Courtesy of David J. Waxman. Used with permission.
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