Sex Differences in the Expression of Hepatic Drug
David J. Waxman and Minita G. Holloway
Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts
Received April 1, 2009; accepted May 29, 2009
Sex differences in pharmacokinetics and pharmacodynamics
characterize many drugs and contribute to individual differ-
ences in drug efficacy and toxicity. Sex-based differences in
drug metabolism are the primary cause of sex-dependent phar-
macokinetics and reflect underlying sex differences in the ex-
pression of hepatic enzymes active in the metabolism of drugs,
steroids, fatty acids and environmental chemicals, including
cytochromes P450 (P450s), sulfotransferases, glutathione
transferases, and UDP-glucuronosyltransferases. Studies in
the rat and mouse liver models have identified more than 1000
genes whose expression is sex-dependent; together, these
genes impart substantial sexual dimorphism to liver metabolic
function and pathophysiology. Sex differences in drug metab-
olism and pharmacokinetics also occur in humans and are due
in part to the female-predominant expression of CYP3A4, the
most important P450 catalyst of drug metabolism in human
liver. The sexually dimorphic expression of P450s and other
liver-expressed genes is regulated by the temporal pattern of
plasma growth hormone (GH) release by the pituitary gland,
which shows significant sex differences. These differences are
most pronounced in rats and mice, where plasma GH profiles
are highly pulsatile (intermittent) in male animals versus more
frequent (nearly continuous) in female animals. This review
discusses key features of the cell signaling and molecular reg-
ulatory mechanisms by which these sex-dependent plasma GH
patterns impart sex specificity to the liver. Moreover, the es-
sential role proposed for the GH-activated transcription factor
signal transducer and activator of transcription (STAT) 5b, and
for hepatic nuclear factor (HNF) 4?, as mediators of the sex-
dependent effects of GH on the liver, is evaluated. Together,
these studies of the cellular, molecular, and gene regulatory
mechanisms that underlie sex-based differences in liver gene
expression have provided novel insights into the physiological
regulation of both xenobiotic and endobiotic metabolism.
Individual differences in drug metabolism and pharmaco-
kinetics contribute to the individual-to-individual variation
that characterizes the responses to many drugs and other
foreign chemicals and presents a major challenge in clinical
pharmacology. Individual variation in the expression of ma-
jor drug-metabolizing enzymes (DMEs), including cyto-
chromes P450 (P450s), sulfotransferases, glutathione trans-
ferases, and UDP-glucuronosyltransferase, is associated
with substantial individual differences in the bioavailability
and clearance of drugs and other xenobiotics. Given the cru-
cial role of hepatic DMEs in regulating the pharmacological
and biological activity of drugs as well as steroid and other
endobiotics, it is important to understand the regulatory
features that lead to individual differences in the expression
of DMEs. Factors that contribute to interindividual differ-
ences in DME expression and drug metabolism include ge-
netic polymorphisms (Hines et al., 2008), prior or concomi-
tant exposure to drugs and environmental chemicals
(Urquhart et al., 2007), dietary factors (Moon et al., 2006;
Murray, 2007), pregnancy (Anderson, 2005a), diseased states
(Mann, 2006), epigenetic factors (Szyf, 2007), and endoge-
nous hormonal factors, which change with age and differ
between male and female subjects (Cotreau et al., 2005;
Genetic polymorphisms of DMEs influence the clinical out-
come of an estimated 20 to 25% of all drug therapies (In-
This work was supported in part by the National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases [Grant
Article, publication date, and citation information can be found at
ABBREVIATIONS: DME, drug-metabolizing enzyme; P450, cytochrome P450; GH, growth hormone; IGF, insulin-like growth factor; STAT, signal
transducer and activator of transcription; JAK, Janus kinase; HNF, hepatic nuclear factor.
Copyright © 2009 The American Society for Pharmacology and Experimental Therapeutics
Mol Pharmacol 76:215–228, 2009
Vol. 76, No. 2
Printed in U.S.A.
gelman-Sundberg, 2004; Eichelbaum et al., 2006). Several
key drug-metabolizing human P450 genes are highly poly-
morphic, with more than 350 distinct alleles identified for the
57 known human P450 genes. A well studied example is
CYP2D6, where genetic polymorphisms contribute to large
interindividual variability in the metabolism of many anti-
drugs (Ingelman-Sundberg et al., 2007). Interindividual dif-
ferences also arise from the induction of P450s and other
DMEs after exposure to lipophilic drugs and environmental
chemicals. For example, phenobarbital and other drugs can
increase the rates of metabolism of many drugs and chemi-
cals by increasing the expression of individual P450 genes
(Waxman and Azaroff, 1992). This P450 induction response
is mediated by ligand-activated transcription factors (nuclear
receptors) that function as sensors of foreign compounds and
can activate a large number of DME genes in liver and other
tissues (Waxman, 1999; Handschin and Meyer, 2003; Timsit
and Negishi, 2007), with the associated potential for drug
interactions (Jana and Paliwal, 2007; Sinz et al., 2008). The
xenobiotic-activated nuclear receptors constitutive andro-
stane receptor, pregnane X-receptor, and peroxisome prolif-
erator-activated receptor-? respond to a wide range of xeno-
chemicals and induce the expression of CYP2B, CYP3A, and
CYP4A genes, respectively. Aryl hydrocarbon receptor is a
receptor/transcription factor that induces CYP1 family mem-
bers and certain other DME genes upon binding polycyclic
aromatic hydrocarbons and other drugs and environmental
chemicals (Ramadoss et al., 2005). Hepatic expression of
DMEs can also be altered by pathophysiological conditions
such as diabetes, inflammation, alcohol consumption, and
protein-calorie malnutrition (Kim and Novak, 2007; Morgan
et al., 2008). In addition, circadian factors regulate the ex-
pression of certain DMEs (Gachon et al., 2006) and contrib-
ute to the dosing time-dependence of drug activity and tox-
icity (Levi and Schibler, 2007).
Sex-based differences1in pharmacokinetics and pharma-
codynamics are well recognized (Fletcher et al., 1994; Gandhi
et al., 2004; Franconi et al., 2007) and can be an important
source of individual differences in drug responses. Sex-based
differences in pharmacokinetics reflect differences in bio-
availability, distribution, metabolism, and/or excretion. Sex
hormones influence bioavailability through effects on gastro-
intestinal motility; estrogen inhibits gastric emptying. Sex
differences in pharmacokinetics can result from sex differ-
ences in distribution, which can be caused by differences in
body weight (lower in women), body fat (higher in women),
plasma volume (lower in women, but varies through the
menstrual cycle and during pregnancy), and organ blood flow
(higher in women). In addition, body-weight effects on glo-
merular filtration rate can contribute to lower renal clear-
ance in women in the case of drugs that are actively elimi-
nated via the kidney (Gandhi et al., 2004). However, sex
differences in metabolism are thought to be the primary
determinant of sex differences in pharmacokinetics. Male-
female differences in the metabolism of barbiturates were
documented in rats as early as 1932 (Nicholas and Barron,
1932) and were later found to characterize many drugs and
steroids, as shown in both rat and mouse models (Kato, 1974;
Skett, 1988). These sex differences in metabolism are now
known to reflect sex differences in the expression of specific,
individual hepatic P450 enzymes and other DMEs (Shapiro
et al., 1995). Sex-linked differences in P450-dependent drug
and steroid metabolism are also found in hamster (Teixeira
and Gil, 1991; Sakuma et al., 1994), dog (Lin et al., 1996; Hay
Kraus et al., 2000), chicken (Pampori and Shapiro, 1993), and
fish (Gray et al., 1991; Lee et al., 1998). Sex differences in
human hepatic P450-catalyzed drug metabolism are well
documented, but are less dramatic than in the rat (Tanaka,
1999; Parkinson et al., 2004; Scandlyn et al., 2008). This
review discusses some of the pharmacological consequences
of the observed sex differences in drug metabolism. The role
of hormones, in particular GH, in establishing and maintain-
ing these sex differences is discussed, and recent mouse and
rat model studies that elucidate the underlying cellular sig-
naling and molecular regulatory mechanisms by which pitu-
itary GH secretory profiles dictate sex-based differences in
DME expression in the liver are evaluated, focusing on fac-
tors that regulate the transcription of genes that code for
Sex Differences in Hepatic Drug Metabolism
Sex-based differences characterize the metabolism of many
drugs commonly used in humans (Gandhi et al., 2004; Ander-
son, 2005b; Schwartz, 2007); 6 to 7% of new drug applications
that include a sex analysis show at least 40% difference in
pharmacokinetics between men and women (Anderson,
2005b). For example, acetaminophen clearance rates are 22%
higher in men than in women because of a higher rate of
glucuronidation (Miners et al., 1983). The higher bioavail-
ability of aspirin in women than in men has been linked to
decreased conjugation with glycine and glucuronic acid
(Franconi et al., 2007). Men show a higher rate of clearance
of the benzodiazepines diazepam, chlordiazepoxide, and olan-
zapine (MacLeod et al., 1979; Roberts et al., 1979; Bigos et
al., 2008). Likewise, women display greater sensitivity to
diazepam, which can lead to impairment of psychomotor
skills (Palva, 1985). CYP3A4, the predominant cytochrome
P450 catalyst of oxidative metabolism in human liver, is
expressed at a higher protein and mRNA level in women
than in men (Hunt et al., 1992; Wolbold et al., 2003; Dicz-
falusy et al., 2008). Accordingly, certain CYP3A4 drug sub-
strates, including cyclosporine (Kahan et al., 1986), erythro-
mycin (Austin et al., 1980), and nifedipine (Krecic-Shepard et
al., 2000), show higher clearance rates in women. CYP3A4-
catalyzed hepatic microsomal N-dechloroethylation of the an-
ticancer drug ifosfamide is also more rapid in women, sug-
gesting that women could be more susceptible to the
neurotoxic side affects associated with this metabolic path-
way (Schmidt et al., 2001). CYP3A4 also metabolizes ste-
roids, such as cortisol, whose conversion to 6?-hydroxycorti-
sol is more rapid in women than in men and serves as a
biomarker for CYP3A4 metabolic activity (Inagaki et al.,
Higher CYP2B6 activity has been observed in women than
in men of Hispanic origin (Lamba et al., 2003). There is also
evidence for higher CYP2A6 activity in women (Sinues et al.,
1Although the term “gender differences” is often used in the medical liter-
ature to describe male-female differences, “sex” is the preferred term when
describing biologically determined physiological, or pathophysiological, differ-
ences between male and female members of a species. “Gender” is a social
construct that refers to an individual’s self-representation as masculine or
feminine, which, unlike “sex,” can be influenced by cultural factors (Gray,
Waxman and Holloway
Moon YJ, Wang X, and Morris ME (2006) Dietary flavonoids: effects on xenobiotic
and carcinogen metabolism. Toxicol In Vitro 20:187–210.
Morgan ET, Goralski KB, Piquette-Miller M, Renton KW, Robertson GR, Chaluvadi
MR, Charles KA, Clarke SJ, Kacevska M, Liddle C, et al. (2008) Regulation of
drug-metabolizing enzymes and transporters in infection, inflammation, and can-
cer. Drug Metab Dispos 36:205–216.
Morgan ET, MacGeoch C, and Gustafsson JA (1985) Hormonal and developmental
regulation of expression of the hepatic microsomal steroid 16 alpha-hydroxylase
cytochrome P-450 apoprotein in the rat. J Biol Chem 260:11895–11898.
Murray M (2007) Role of signalling systems in the effects of dietary factors on the
expression of mammalian CYPs. Expert Opin Drug Metab Toxicol 3:185–196.
Nakayama K, Sudo Y, Sasaki Y, Iwata H, Takahashi M, and Kamataki T (2001)
Studies on transcriptional regulation of Cyp3a16 gene in mouse livers by applica-
tion of direct DNA injection method. Biochem Biophys Res Commun 287:820–824.
Nicholas JS and Barron DH (1932) The use of sodium amytal in the production of
anesthesia in the rat. J Pharmacol Exp Ther 46:125–129.
Odom DT, Dowell RD, Jacobsen ES, Gordon W, Danford TW, MacIsaac KD, Rolfe PA,
Conboy CM, Gifford DK, and Fraenkel E (2007) Tissue-specific transcriptional
regulation has diverged significantly between human and mouse. Nat Genet 39:
Ofotokun I (2005) Sex differences in the pharmacologic effects of antiretroviral
drugs: potential roles of drug transporters and phase 1 and 2 metabolizing en-
zymes. Top HIV Med 13:79–83.
Ono M, Chia DJ, Merino-Martinez R, Flores-Morales A, Unterman TG, and Rotwein
P (2007) Signal transducer and activator of transcription (Stat) 5b-mediated inhi-
bition of insulin-like growth factor binding protein-1 gene transcription: a mech-
anism for repression of gene expression by growth hormone. Mol Endocrinol
Oscarsson J, Olofsson SO, Vikman K, and Ede ´n S (1991) Growth hormone regulation
of serum lipoproteins in the rat: different growth hormone regulatory principles for
apolipoprotein (apo) B and the sexually dimorphic apo E concentrations. Metabo-
Palva ES (1985) Gender-related differences in diazepam effects on performance. Med
Pampori NA, Agrawal AK, and Shapiro BH (1991) Renaturalizing the sexually
dimorphic profiles of circulating growth hormone in hypophysectomized rats. Acta
Endocrinol (Copenh) 124:283–289.
Pampori NA and Shapiro BH (1993) Sexual dimorphism in avian hepatic monooxy-
genases. Biochem Pharmacol 46:885–890.
Pampori NA and Shapiro BH (1996) Feminization of hepatic cytochrome P450s by
nominal levels of growth hormone in the feminine plasma profile. Mol Pharmacol
Pampori NA and Shapiro BH (1999) Gender differences in the responsiveness of the
sex-dependent isoforms of hepatic P450 to the feminine plasma growth hormone
profile. Endocrinology 140:1245–1254.
Park SH and Waxman DJ (2001) Inhibitory cross-talk between STAT5b and liver
nuclear factor HNF3beta. Impact on the regulation of growth hormone pulse-
stimulated, male-specific liver cytochrome P-450 gene expression. J Biol Chem
Park SH, Wiwi CA, and Waxman DJ (2006) Signalling cross-talk between hepatocyte
nuclear factor 4alpha and growth-hormone-activated STAT5b. Biochem J 397:
Parkinson A, Mudra DR, Johnson C, Dwyer A, and Carroll KM (2004) The effects of
gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in
human liver microsomes and inducibility in cultured human hepatocytes. Toxicol
Appl Pharmacol 199:193–209.
Rademaker M (2001) Do women have more adverse drug reactions? Am J Clin
Ram PA, Park SH, Choi HK, and Waxman DJ (1996) Growth hormone activation of
Stat 1, Stat 3, and Stat 5 in rat liver. Differential kinetics of hormone desensiti-
zation and growth hormone stimulation of both tyrosine phosphorylation and
serine/threonine phosphorylation. J Biol Chem 271:5929–5940.
Ram PA and Waxman DJ (1999) SOCS/CIS protein inhibition of growth hormone-
stimulated STAT5 signaling by multiple mechanisms. J Biol Chem 274:35553–
Ram PA and Waxman DJ (2000) Role of the cytokine-inducible SH2 protein CIS in
desensitization of STAT5b signaling by continuous growth hormone. J Biol Chem
Ramadoss P, Marcus C, and Perdew GH (2005) Role of the aryl hydrocarbon receptor
in drug metabolism. Expert Opin Drug Metab Toxicol 1:9–21.
Roberts RK, Desmond PV, Wilkinson GR, and Schenker S (1979) Disposition of
chlordiazepoxide: sex differences and effects of oral contraceptives. Clin Pharma-
col Ther 25:826–831.
Robertson JA, Haldose ´n LA, Wood TJ, Steed MK, and Gustafsson JA (1990) Growth
hormone pretranslationally regulates the sexually dimorphic expression of the
prolactin receptor gene in rat liver. Mol Endocrinol 4:1235–1239.
Rogers AB, Theve EJ, Feng Y, Fry RC, Taghizadeh K, Clapp KM, Boussahmain C,
Cormier KS, and Fox JG (2007) Hepatocellular carcinoma associated with liver-
gender disruption in male mice. Cancer Res 67:11536–11546.
Rosenfeld RG, Belgorosky A, Camacho-Hubner C, Savage MO, Wit JM, and Hwa V
(2007) Defects in growth hormone receptor signaling. Trends Endocrinol Metab
Rowland JE, Lichanska AM, Kerr LM, White M, d’Aniello EM, Maher SL, Brown R,
Teasdale RD, Noakes PG, and Waters MJ (2005) In vivo analysis of growth
hormone receptor signaling domains and their associated transcripts. Mol Cell
Rowlinson SW, Yoshizato H, Barclay JL, Brooks AJ, Behncken SN, Kerr LM, Millard
K, Palethorpe K, Nielsen K, Clyde-Smith J, et al. (2008) An agonist-induced
conformational change in the growth hormone receptor determines the choice of
signalling pathway. Nat Cell Biol 10:740–747.
Rudling M, Norstedt G, Olivecrona H, Reihne ´r E, Gustafsson JA, and Angelin B
(1992) Importance of growth hormone for the induction of hepatic low density
lipoprotein receptors. Proc Natl Acad Sci U S A 89:6983–6987.
Rumbaugh RC and Colby HD (1980) Is growth hormone the pituitary feminizing
factor mediating the actions of estradiol on hepatic drug and steroid metabolism?
Sakuma T, Endo Y, Mashino M, Kuroiwa M, Ohara A, Jarukamjorn K, and Nemoto
N (2002) Regulation of the expression of two female-predominant CYP3A mRNAs
(CYP3A41 and CYP3A44) in mouse liver by sex and growth hormones. Arch
Biochem Biophys 404:234–242.
Sakuma T, Masaki K, Itoh S, Yokoi T, and Kamataki T (1994) Sex-related differences
in the expression of cytochrome P450 in hamsters: cDNA cloning and examination
of the expression of three distinct CYP2C cDNAs. Mol Pharmacol 45:228–236.
Sasaki Y, Takahashi Y, Nakayama K, and Kamataki T (1999) Cooperative regulation
of CYP2C12 gene expression by STAT5 and liver-specific factors in female rats.
J Biol Chem 274:37117–37124.
Scandlyn MJ, Stuart EC, and Rosengren RJ (2008) Sex-specific differences in
CYP450 isoforms in humans. Expert Opin Drug Metab Toxicol 4:413–424.
Schmidt R, Baumann F, Hanschmann H, Geissler F, and Preiss R (2001) Gender
difference in ifosfamide metabolism by human liver microsomes. Eur J Drug
Metab Pharmacokinet 26:193–200.
Schwartz JB (2007) The current state of knowledge on age, sex, and their interac-
tions on clinical pharmacology. Clin Pharmacol Ther 82:87–96.
Shapiro BH, Agrawal AK, and Pampori NA (1995) Gender differences in drug
metabolism regulated by growth hormone. Int J Biochem Cell Biol 27:9–20.
Shimizu I, Kohno N, Tamaki K, Shono M, Huang HW, He JH, and Yao DF (2007)
Female hepatology: favorable role of estrogen in chronic liver disease with hepa-
titis B virus infection. World J Gastroenterol 13:4295–4305.
Sinues B, Fanlo A, Mayayo E, Carcas C, Vicente J, Arenaz I, and Cebollada A (2008)
CYP2A6 activity in a healthy Spanish population: effect of age, sex, smoking, and
oral contraceptives. Hum Exp Toxicol 27:367–372.
Sinz M, Wallace G, and Sahi J (2008) Current industrial practices in assessing
CYP450 enzyme induction: preclinical and clinical. Aaps J 10:391–400.
Sjo ¨gren K, Liu JL, Blad K, Skrtic S, Vidal O, Wallenius V, LeRoith D, To ¨rnell J,
Isaksson OG, Jansson JO, et al. (1999) Liver-derived insulin-like growth factor I
(IGF-I) is the principal source of IGF-I in blood but is not required for postnatal
body growth in mice. Proc Natl Acad Sci U S A 96:7088–7092.
Skett P (1988) Biochemical basis of sex differences in drug metabolism. Pharmacol
Sladek FM (1994) Orphan receptor HNF-4 and liver-specific gene expression. Recep-
Soldaini E, John S, Moro S, Bollenbacher J, Schindler U, and Leonard WJ (2000)
DNA binding site selection of dimeric and tetrameric Stat5 proteins reveals a large
repertoire of divergent tetrameric Stat5a binding sites. Mol Cell Biol 20:389–401.
Song WC and Melner MH (2000) Steroid transformation enzymes as critical regu-
lators of steroid action in vivo. Endocrinology 141:1587–1589.
Srivastava PK and Waxman DJ (1993) Sex-dependent expression and growth hor-
mone regulation of class alpha and class mu glutathione S-transferase mRNAs in
adult rat liver. Biochem J 294:159–165.
Stro ¨m A, Eguchi H, Mode A, Legraverend C, Tollet P, Stro ¨mstedt PE, and Gustafs-
son JA (1994) Characterization of the proximal promoter and two silencer ele-
ments in the CYP2C11 gene expressed in rat liver. DNA Cell Biol 13:805–819.
Sueyoshi T, Yokomori N, Korach KS, and Negishi M (1999) Developmental action of
estrogen receptor-alpha feminizes the growth hormone-Stat5b pathway and ex-
pression of Cyp2a4 and Cyp2d9 genes in mouse liver. Mol Pharmacol 56:473–477.
Sundseth SS and Waxman DJ (1992) Sex-dependent expression and clofibrate in-
ducibility of cytochrome P450 4A fatty acid omega-hydroxylases. Male specificity of
liver and kidney CYP4A2 mRNA and tissue-specific regulation by growth hormone
and testosterone. J Biol Chem 267:3915–3921.
Szyf M (2007) The dynamic epigenome and its implications in toxicology. Toxicol Sci
Takeuchi T, Tsutsumi O, Nakamura N, Ikezuki Y, Takai Y, Yano T, and Taketani Y
(2004) Gender difference in serum bisphenol A levels may be caused by liver
UDP-glucuronosyltransferase activity in rats. Biochem Biophys Res Commun 325:
Tanaka E (1999) Gender-related differences in pharmacokinetics and their clinical
significance. J Clin Pharm Ther 24:339–346.
Tannenbaum GS, Choi HK, Gurd W, and Waxman DJ (2001) Temporal relationship
between the sexually dimorphic spontaneous GH secretory profiles and hepatic
STAT5 activity. Endocrinology 142:4599–4606.
Tannenbaum GS and Martin JB (1976) Evidence for an endogenous ultradian
rhythm governing growth hormone secretion in the rat. Endocrinology 98:562–
Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M,
Bodner S, Grosveld G, and Ihle JN (1998) Stat5a and Stat5b proteins have
essential and nonessential, or redundant, roles in cytokine responses. Cell 93:841–
Teixeira J and Gil G (1991) Cloning, expression, and regulation of lithocholic acid 6
beta-hydroxylase. J Biol Chem 266:21030–21036.
Thangavel C, Dworakowski W, and Shapiro BH (2006) Inducibility of male-specific
isoforms of cytochrome p450 by sex-dependent growth hormone profiles in hepa-
tocyte cultures from male but not female rats. Drug Metab Dispos 34:410–419.
Thangavel C, Garcia MC, and Shapiro BH (2004) Intrinsic sex differences determine
expression of growth hormone-regulated female cytochrome P450s. Mol Cell En-
Thangavel C and Shapiro BH (2007) A molecular basis for the sexually dimorphic
response to growth hormone. Endocrinology 148:2894–2903.
Timsit YE and Negishi M (2007) CAR and PXR: the xenobiotic-sensing receptors.
Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, and
Sex Differences in Liver DMEs
Davey HW (1997) Requirement of STAT5b for sexual dimorphism of body growth
rates and liver gene expression. Proc Natl Acad Sci U S A 94:7239–7244.
Urquhart BL, Tirona RG, and Kim RB (2007) Nuclear receptors and the regulation
of drug-metabolizing enzymes and drug transporters: implications for interindi-
vidual variability in response to drugs. J Clin Pharmacol 47:566–578.
Veldhuis JD (1998) Neuroendocrine control of pulsatile growth hormone release in
the human: relationship with gender. Growth Horm IGF Res 8 (Suppl B):49–59.
Veldhuis JD and Bowers CY (2003) Human GH pulsatility: an ensemble property
regulated by age and gender. J Endocrinol Invest 26:799–813.
Vidal OM, Merino R, Rico-Bautista E, Fernandez-Perez L, Chia DJ, Woelfle J, Ono
M, Lenhard B, Norstedt G, Rotwein P, et al. (2007) In vivo transcript profiling and
phylogenetic analysis identifies suppressor of cytokine signaling 2 as a direct
signal transducer and activator of transcription 5b target in liver. Mol Endocrinol
Vidarsdottir S, Walenkamp MJ, Pereira AM, Karperien M, van Doorn J, van Duyv-
envoorde HA, White S, Breuning MH, Roelfsema F, Kruithof MF, et al. (2006)
Clinical and biochemical characteristics of a male patient with a novel homozygous
STAT5b mutation. J Clin Endocrinol Metab 91:3482–3485.
Wallenius K, Sjo ¨gren K, Peng XD, Park S, Wallenius V, Liu JL, Umaerus M, Wennbo
H, Isaksson O, Frohman L, et al. (2001) Liver-derived IGF-I regulates GH secre-
tion at the pituitary level in mice. Endocrinology 142:4762–4770.
Wang J and Huang Y (2007) Pharmacogenomics of sex difference in chemotherapeu-
tic toxicity. Curr Drug Discov Technol 4:59–68.
Wang Y and Jiang H (2005) Identification of a distal STAT5-binding DNA region
that may mediate growth hormone regulation of insulin-like growth factor-I gene
expression. J Biol Chem 280:10955–10963.
Watkins PB, Turgeon DK, Jaffe CA, Ho PJ, and Barkan AL (1993) Pulsation
frequency of growth hormone may mediate gender differences in CYP3A activity in
man (Abstract). Clin Res 41:13219.
Wauthier V and Waxman DJ (2008) Sex-specific early growth hormone response
genes in rat liver. Mol Endocrinol 22:1962–1974.
Waxman DJ (1988) Interactions of hepatic cytochromes P-450 with steroid hor-
mones. Regioselectivity and stereospecificity of steroid metabolism and hormonal
regulation of rat P-450 enzyme expression. Biochem Pharmacol 37:71–84.
Waxman DJ (1999) P450 gene induction by structurally diverse xenochemicals:
central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys
Waxman DJ and Azaroff L (1992) Phenobarbital induction of cytochrome P-450 gene
expression. Biochem J 281:577–592.
Waxman DJ, LeBlanc GA, Morrissey JJ, Staunton J, and Lapenson DP (1988) Adult
male-specific and neonatally programmed rat hepatic P-450 forms RLM2 and 2a
are not dependent on pulsatile plasma growth hormone for expression. J Biol
Waxman DJ and O’Connor C (2006) Growth hormone regulation of sex-dependent
liver gene expression. Mol Endocrinol 20:2613–2629.
Waxman DJ, Pampori NA, Ram PA, Agrawal AK, and Shapiro BH (1991) Interpulse
interval in circulating growth hormone patterns regulates sexually dimorphic
expression of hepatic cytochrome P450. Proc Natl Acad Sci U S A 88:6868–6872.
Waxman DJ, Ram PA, Park SH, and Choi HK (1995) Intermittent plasma growth
hormone triggers tyrosine phosphorylation and nuclear translocation of a liver-
expressed, Stat 5-related DNA binding protein. Proposed role as an intracellular
regulator of male-specific liver gene transcription. J Biol Chem 270:13262–13270.
Wilson JT (1973) Growth hormone modulation of liver drug metabolic enzyme
activity in the rat. I. Effect of the hormone on the content and rate of reduction of
microsomal cytochrome P-450. Biochem Pharmacol 22:1717–1728.
Wilson JT and Bass A (1973) Growth hormone modulation of liver drug metabolic
enzyme activity in the rat. II. Specificity of the hormone effect. Proc Soc Exp Biol
Wiwi CA, Gupte M, and Waxman DJ (2004) Sexually dimorphic P450 gene expres-
sion in liver-specific hepatocyte nuclear factor 4alpha-deficient mice. Mol Endo-
Wiwi CA and Waxman DJ (2005) Role of hepatocyte nuclear factors in transcrip-
tional regulation of male-specific CYP2A2. J Biol Chem 280:3259–3268.
Wolbold R, Klein K, Burk O, Nu ¨ssler AK, Neuhaus P, Eichelbaum M, Schwab M, and
Zanger UM (2003) Sex is a major determinant of CYP3A4 expression in human
liver. Hepatology 38:978–988.
Yamazoe Y, Shimada M, Murayama N, Kawano S, and Kato R (1986) The regulation
by growth hormone of microsomal testosterone 6 beta-hydroxylase in male rat
livers. J Biochem 100:1095–1097.
Yang X, Schadt EE, Wang S, Wang H, Arnold AP, Ingram-Drake L, Drake TA, and
Lusis AJ (2006) Tissue-specific expression and regulation of sexually dimorphic
genes in mice. Genome Res 16:995–1004.
Yokomori N, Nishio K, Aida K, and Negishi M (1997) Transcriptional regulation by
HNF-4 of the steroid 15alpha-hydroxylase P450 (Cyp2a-4) gene in mouse liver. J
Steroid Biochem Mol Biol 62:307–314.
Yokoyama Y, Nimura Y, Nagino M, Bland KI, and Chaudry IH (2005) Current
understanding of gender dimorphism in hepatic pathophysiology. J Surg Res
You L (2004) Steroid hormone biotransformation and xenobiotic induction of hepatic
steroid metabolizing enzymes. Chem Biol Interact 147:233–246.
Address correspondence to: David J. Waxman, Department of Biology,
Boston University, 5 Cummington Street, Boston, MA 02215. Email: djw@
Waxman and Holloway